US10086012B2 - Control and characterization of memory function - Google Patents

Control and characterization of memory function Download PDF

Info

Publication number
US10086012B2
US10086012B2 US13/882,705 US201113882705A US10086012B2 US 10086012 B2 US10086012 B2 US 10086012B2 US 201113882705 A US201113882705 A US 201113882705A US 10086012 B2 US10086012 B2 US 10086012B2
Authority
US
United States
Prior art keywords
light
memory
neurons
mice
hippocampus
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Active, expires
Application number
US13/882,705
Other languages
English (en)
Other versions
US20130343998A1 (en
Inventor
Karl Deisseroth
Inbal Goshen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Leland Stanford Junior University
Original Assignee
Leland Stanford Junior University
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Leland Stanford Junior University filed Critical Leland Stanford Junior University
Priority to US13/882,705 priority Critical patent/US10086012B2/en
Assigned to THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY reassignment THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIOR UNIVERSITY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: DEISSEROTH, KARL, GOSHEN, INBAL
Publication of US20130343998A1 publication Critical patent/US20130343998A1/en
Application granted granted Critical
Publication of US10086012B2 publication Critical patent/US10086012B2/en
Active legal-status Critical Current
Adjusted expiration legal-status Critical

Links

Images

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K67/00—Rearing or breeding animals, not otherwise provided for; New breeds of animals
    • A01K67/027—New breeds of vertebrates
    • A01K67/0275—Genetically modified vertebrates, e.g. transgenic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01K—ANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00—Genetically modified animals
    • A01K2217/05—Animals comprising random inserted nucleic acids (transgenic)
    • A01K2217/052—Animals comprising random inserted nucleic acids (transgenic) inducing gain of function
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/04—Fusion polypeptide containing a localisation/targetting motif containing an ER retention signal such as a C-terminal HDEL motif
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/01—Fusion polypeptide containing a localisation/targetting motif
    • C07K2319/10—Fusion polypeptide containing a localisation/targetting motif containing a tag for extracellular membrane crossing, e.g. TAT or VP22

Definitions

  • the consolidation of remote memories relies on both synaptic consolidation processes on the timescale of minutes to hours, and circuit consolidation over weeks to years (Frankland and Bontempi, 2005; Squire and Bayley, 2007).
  • the process of long-term contextual fear memory consolidation requires early involvement of the hippocampus, followed by the neocortex; in the course of this process, an influence of hippocampus on neocortex may enable the hippocampus to facilitate the long-term cortical storage of memory, rather than stably store the memory itself.
  • hippocampal lesions impair recent memory one day after training, but the same lesions had no effect on remote memory, several weeks after training (Anagnostaras et al., 1999; Bontempi et al., 1999; Debiec et al., 2002; Frankland et al., 2004; Kim and Fanselow, 1992; Kitamura et al., 2009; Maren et al., 1997; Maviel et al., 2004; Shimizu et al., 2000; Wang et al., 2003; Winocur et al., 2009). Additional studies suggest that both hippocampal and cortical memories are in continuous interplay.
  • amnesia e.g., non-graded, graded retrograde, focal retrograde amnesia, etc.
  • PTSD post traumatic stress disorder
  • PTSD is a common debilitating psychiatric condition in which a single exposure to a traumatic event can lead to years of compromised function due to repeated re-experiencing of the trauma. Understanding the neural pathways that underlie undesired memory recall may help aid in the discovery and screening of pharmacological therapies to treat patients with such memory disorders.
  • aspects of the present disclosure relates to control or characterization of memory function in living animals, as described herein. While the present disclosure is not necessarily limited in these contexts, embodiments of the invention may be appreciated through a discussion of examples using these and other contexts.
  • Certain embodiments of the present disclosure are directed toward specially-targeted circuits that are associated with memory function. More particular embodiments relate to spatio-temporal control over neural circuitry to identify specific circuit targets associated and corresponding with memory function(s) (e.g., memory formation and/or retrieval).
  • Particular embodiments of the present disclosure are directed toward temporally precise inhibition of neural circuits in the hippocampus (such as the neurons of the dorsal CA1 field of the hippocampus), the precision being sufficient to disrupt memory function. It has been discovered that temporal precision of neural inhibition is effective to disrupt remote memory retrieval, whereas prolonged inhibition has no significant effect on remote memory retrieval. Accordingly, aspects of the present disclosure relate to temporal aspects of such inhibition.
  • methods for reversibly affecting memory function may comprise temporarily inhibiting neurons of the amygdala (e.g. basolateral amygdala) and/or neurons of the cingulate cortex (e.g., anterior cingulated cortex).
  • this inhibition is performed using an optogenetic system that involves the expression of light-activated proteins (e.g., opsins) in the cells of the neural circuit.
  • the inhibition can be performed using direct electrical stimulus. Still other embodiments allow for the use of temporally-precise pharmaceuticals.
  • Various embodiments of the present disclosure relate to an optogenetic system or method that correlates temporal control over a neural circuit with measurable metrics. For instance, a particular memory function might be associated with a neurological disorder.
  • the optogenetic system targets a neural circuit within an individual for selective control thereof.
  • the optogenetic system involves monitoring the individual for metrics (e.g., symptoms) associated with the neurological disorder. In this manner the optogenetic system can provide detailed information about the neural circuit, its function and/or the neurological disorder.
  • One or more methods for reversibly affecting memory function may be used to evaluate the effectiveness of pharmacological agents in treating PTSD and/or various memory disorders.
  • the light-activated proteins may be configured to inhibit depolarization of a neuron in the presence of light having a specific wavelength. In some variations, the light-activated proteins may be configured to promote depolarization of a neuron in the presence of a light having a specific wavelength.
  • non-human animal comprising a light-activated protein expressed on the cell membrane of excitatory neurons in the dorsal CA1 field of the hippocampus of the animal, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, wherein the illumination of the protein reversibly affects memory function.
  • a non-human animal comprising a light-activated protein expressed on the cell membrane of excitatory neurons in the anterior cingulated cortex of the animal, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, wherein the illumination of the protein reversibly affects memory function.
  • non-human animal comprising a light-activated protein expressed on the cell membrane of excitatory neurons in the basolateral amygdala of the animal, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, wherein the illumination of the protein reversibly affects memory function.
  • the memory function that is affected when the neurons are illuminated may be memory retrieval and/or memory formation.
  • the memory is a fearful memory and/or a remote memory.
  • a brain tissue slice comprising a brain region selected from the group consisting of the dorsal CA1 field of the hippocampus, the basolateral amygdala, and the anterior cingulated cortex, wherein a light-activated protein is expressed on the cell membrane of excitatory neurons of the brain region, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, wherein the illumination of the protein reversibly affects memory function.
  • the method for reversibly affecting memory retrieval or formation in an individual comprises: administering a polynucleotide encoding a light-activated protein to the dorsal CA1 field of the hippocampus in the individual, wherein light-activated protein is expressed on the cell membrane of the excitatory neurons in the dorsal CA1 field of the hippocampus and the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, whereby activating the protein by the light reversibly affects memory retrieval or formation of an event in the individual.
  • the method for reversibly affecting memory retrieval or formation comprises: inhibiting depolarization of excitatory neurons in the dorsal CA1 field of the hippocampus during memory retrieval or formation of an event in an individual, wherein a light-activated protein is expressed on the cell membrane of the excitatory neurons in the dorsal CA1 field of the hippocampus of the individual, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light.
  • the method for reversibly affecting memory retrieval or formation in an individual comprises: administering a polynucleotide encoding a light-activated protein to the anterior cingulated cortex in the individual, wherein light-activated protein is expressed on the cell membrane of the excitatory neurons in the anterior cingulated cortex and the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, whereby activating the protein by the light reversibly affects memory retrieval or formation of an event in the individual.
  • the method for reversibly affecting memory retrieval or formation comprises: inhibiting depolarization of excitatory neurons in the anterior cingulated cortex during memory retrieval or formation of an event in an individual, wherein a light-activated protein is expressed on the cell membrane of the excitatory neurons in the anterior cingulated cortex of the individual, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light.
  • the method for reversibly affecting memory retrieval or formation in an individual comprises: administering a polynucleotide encoding a light-activated protein to the basolateral amygdala in the individual, wherein light-activated protein is expressed on the cell membrane of the excitatory neurons in the basolateral amygdala and the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, whereby activating the protein by the light reversibly affects memory retrieval or formation of an event in the individual.
  • the method for reversibly affecting memory retrieval or formation comprises: inhibiting depolarization of excitatory neurons in the basolateral amygdala during memory retrieval or formation of an event in an individual, wherein a light-activated protein is expressed on the cell membrane of the excitatory neurons in the basolateral amygdala of the individual, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light.
  • the method for treating post-traumatic stress disorder in an individual comprises: administering a polynucleotide encoding a light-activated protein to the dorsal CA1 field of the hippocampus in the individual, wherein light-activated protein is expressed on the cell membrane of the excitatory neurons in the dorsal CA1 field of the hippocampus and the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, whereby activating the protein by the light reversibly affects memory retrieval or formation of an event in the individual.
  • the method for treating post-traumatic stress disorder in an individual comprises: administering a polynucleotide encoding a light-activated protein to the anterior cingulated cortex in the individual, wherein light-activated protein is expressed on the cell membrane of the excitatory neurons in the anterior cingulated cortex and the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, whereby activating the protein by the light reversibly affects memory retrieval or formation of an event in the individual.
  • Also provided herein are methods of screening a pharmacological agent that affects memory retrieval or formation comprising: a) contacting excitatory neurons in the dorsal CA1 field of the hippocampus during memory retrieval or formation of an event in a non-human animal with a pharmacological agent, wherein the non-human animal comprises a light-activated protein expressed on the cell membrane of excitatory neurons in the dorsal CA1 field of the hippocampus of the animal, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light; b) inhibiting depolarization of the excitatory neurons in the dorsal CA1 field of the hippocampus during memory retrieval or formation of an event; and c) determining if the pharmacological agent affects memory retrieval or formation in the presence or absence of the light.
  • Also provided herein are methods of screening a pharmacological agent that affects memory retrieval or formation comprising: a) contacting excitatory neurons in the anterior cingulated cortex during memory retrieval or formation of an event in a non-human animal with a pharmacological agent, wherein the non-human animal comprises a light-activated protein expressed on the cell membrane of excitatory neurons in the anterior cingulated cortex of the animal, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light; b) inhibiting depolarization of the excitatory neurons in the anterior cingulated cortex during memory retrieval or formation of an event; and c) determining if the pharmacological agent affects memory retrieval or formation in the presence or absence of the light.
  • Also provided herein are methods of screening a pharmacological agent that affects memory retrieval or formation comprising: a) contacting excitatory neurons in the basolateral amygdala during memory retrieval or formation of an event in a non-human animal with a pharmacological agent, wherein the non-human animal comprises a light-activated protein expressed on the cell membrane of excitatory neurons in the basolateral amygdala of the animal, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light; b) inhibiting depolarization of the excitatory neurons in the basolateral amygdala during memory retrieval or formation of an event; and c) determining if the pharmacological agent affects memory retrieval or formation in the presence or absence of the light.
  • the light-activated protein may be responsive to light and configured such that the protein is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light.
  • the light-activated protein may be selected from the group consisting of NpHR, BR, AR, and GtR3 described herein.
  • the light-activated protein is a NpHR protein comprising an amino acid sequence at least 95%, at least 96%, at least 97%, at least 98%, at least 99% or 100% identical to the sequence shown in SEQ ID NO:3.
  • the NpHR protein further comprises an endoplasmic reticulum (ER) export signal and/or a membrane trafficking signal.
  • ER endoplasmic reticulum
  • the NpHR protein comprises an amino acid sequence at least 95% identical to the sequence shown in SEQ ID NO:3 and an endoplasmic reticulum (ER) export signal.
  • the amino acid sequence at least 95% identical to the sequence shown in SEQ ID NO:3 is linked to the ER export signal through a linker.
  • the ER export signal comprises the amino acid sequence FXYENE (SEQ ID NO:8), where X can be any amino acid.
  • the ER export signal comprises the amino acid sequence VXXSL, where X can be any amino acid.
  • the ER export signal comprises the amino acid sequence FCYENEV (SEQ ID NO:9).
  • the NpHR protein comprises an amino acid sequence at least 95% identical to the sequence shown in SEQ ID NO:3, an ER export signal, and a membrane trafficking signal. In other embodiments, the NpHR protein comprises, from the N-terminus to the C-terminus, the amino acid sequence at least 95% identical to the sequence shown in SEQ ID NO:3, the ER export signal, and the membrane trafficking signal. In other embodiments, the NpHR protein comprises, from the N-terminus to the C-terminus, the amino acid sequence at least 95% identical to the sequence shown in SEQ ID NO:3, the membrane trafficking signal, and the ER export signal. In some embodiments, the membrane trafficking signal is derived from the amino acid sequence of the human inward rectifier potassium channel Kir2.1.
  • the membrane trafficking signal comprises the amino acid sequence K S R I T S E G E Y I P L D Q I D I N V (SEQ ID NO:10).
  • the membrane trafficking signal is linked to the amino acid sequence at least 95% identical to the sequence shown in SEQ ID NO:3 by a linker.
  • the membrane trafficking signal is linked to the ER export signal through a linker.
  • the linker may comprise any of 5, 10, 20, 30, 40, 50, 75, 100, 125, 150, 175, 200, 225, 250, 275, 300, 400, or 500 amino acids in length.
  • the linker may further comprise a fluorescent protein, for example, but not limited to, a yellow fluorescent protein, a red fluorescent protein, a green fluorescent protein, or a cyan fluorescent protein.
  • the light-activated protein further comprises an N-terminal signal peptide.
  • the light-activated protein comprises the amino acid sequence of SEQ ID NO:5.
  • the light-activated protein comprises the amino acid sequence of SEQ ID NO:6.
  • FIG. 1 depicts one variation of a device or a system that may be used to apply light of selected wavelengths to affect memory function.
  • FIG. 2 depicts a flow diagram for modifying memory function.
  • FIGS. 3A and 3B depict variations of methods for evaluating the effects of a test pharmacological agent on neural circuits that underlie memory function.
  • FIGS. 4A-D depicts experimental data showing specific optogenetic inhibition of excitatory neurons in dorsal CA1 reduces neuronal activity.
  • FIG. 4A shows that double lentiviral injection resulted in eNpHR3.1 expression throughout the CA1 only.
  • FIG. 4B shows that eNpHR3.1 is expressed in the neuronal membrane around the soma, as well as in the apical and basal dendrites of CA1 neurons.
  • FIG. 4C depicts data demonstrating that CaMKII ⁇ ::eNpHR3.1 was expressed in 94% (458/486 cells, from 3 mice) of CA1 pyramidal neurons, with 100% specificity (all eNpHR3.1-EYFP cells were CaMKII ⁇ positive).
  • FIG. 4A shows that double lentiviral injection resulted in eNpHR3.1 expression throughout the CA1 only.
  • FIG. 4B shows that eNpHR3.1 is expressed in the neuronal membrane around the soma, as well as in the ap
  • 4D depicts data from in-vivo ‘optrode’ light administration and recording performed by inserting an optic fiber coupled to a tungsten electrode to the CA1 in anesthetized mice expressing eNpHR3.1 (left). 561 nm illumination of CA1 neurons in these mice resulted in a reversible, marked reduction in spiking frequency (4.93 ⁇ 1.6 Hz, 1.31 ⁇ 0.15 Hz, and 6.45 ⁇ 2.4 Hz; before, during and after light administration, respectively, in 15 traces from 2 mice, P ⁇ 0.02), without affecting average spike amplitude (33.55 ⁇ 4.94 ⁇ V, 29.20 ⁇ 4.4 ⁇ V, and 33.32 ⁇ 5.45 ⁇ V; before, during and after light). A representative optrode recording trace, as well as average frequency and amplitude are shown (mean ⁇ SEM).
  • FIGS. 5A-5I depicts experimental data showing that real time CA1 optogenetic inhibition blocks contextual fear acquisition and retrieval.
  • FIG. 5A shows that bilateral in-vivo light may be administered to CA1 by inserting a double optic fiber through bilateral cannula guide in freely-moving mice.
  • FIG. 5B top depicts an experimental sequence where continuous 561 nm illumination was administered during fear-conditioning training, and mice were tested for their memory 24 hr later without light. One day later, mice were re-trained without light, and re-tested without light on the fourth day and with light on the fifth.
  • CA1 optogenetic inhibition also had no effect on exploration of a novel environment.
  • FIG. 5G shows that there was no effect on anxiety, as the percent of time that control and eNpHR3.1 mice spent in the center of the open field was similar (23.8 ⁇ 12.76% vs. 20.46 ⁇ 5.97%, P>0.5). Representative exploration traces are presented.
  • FIG. 5H depicts eNpHR3.0 expression in basolateral amygdala (BLA).
  • FIGS. 6A-6E depicts experimental data showing that CA1 optogenetic inhibition reversibly interferes with remote fear memory recall.
  • FIGS. 7A-7C depicts experimental data showing that precise, but not prolonged CA1 optogenetic inhibition blocks remote contextual fear recall.
  • FIG. 8 depicts experimental data showing that CA1 optogenetic inhibition interferes with ongoing fear recall.
  • This recall disruption did not result in memory erasure, as when the same mice were re-introduced to the conditioning context with no illumination they again demonstrated intact fear response (61.5 ⁇ 6.7 vs. 58.3 ⁇ 3.5% freezing; P>0.5).
  • the fear response abruptly ceased (65.2 ⁇ 6.9 vs. 15.9 ⁇ 5.2% freezing; P ⁇ 0.001).
  • FIG. 9A-9H depicts experimental data showing brain-wide mapping of circuit activity controlled by the hippocampus during remote recall.
  • FIG. 9A depicts an experiment where mice were fear-conditioned under light delivery, and brains were collected 90 min after training.
  • FIG. 9B shows brain slices stained for c-Fos and DAPI. Expression of YFP control and eNpHR3.1 are shown. The CA1 region from which these images were taken is marked by a white square in FIG. 9C .
  • FIG. 9C depicts representative images of CA1, ACC and BLA. Anatomy is shown by DAPI nuclear staining, and the margins of the amygdala are marked with a dashed yellow line.
  • White scalebar 150 ⁇ m.
  • FIG. 9E depicts an experiment where another group of mice was trained, and then re-exposed to the conditioning context 28 days after conditioning. Brains were collected for staining 90 min after testing.
  • FIG. 9F depicts representative CA1, ACC and BLA images following remote memory are shown. White scalebar: 150 ⁇ m.
  • FIG. 9G shows that remote recall 28 days following conditioning resulted in a small but significant increase in CA1 c-Fos expression in control mice (P ⁇ 0.005), and highly increased activity levels in ACC (P ⁇ 0.0001) and BLA (P ⁇ 0.0001). Light inhibition during exposure to the context completely blocked CA1 activity (P ⁇ 0.05), and significantly reduced ACC and BLA activity (P ⁇ 0.0001 and P ⁇ 0.0001, respectively), compared to control.
  • FIG. 9H shows global patterns in brain activity between conditioning (day 0) and remote recall (day 28). Activity levels in CA1 significantly decreased in control (P ⁇ 0.005) mice from day 0 to day 28.
  • Activity levels in ACC significantly increased in both control (P ⁇ 0.0001) and eNpHR3.1 (P ⁇ 0.001) mice day 0 to day 28.
  • Activity levels in BLA significantly increased in control (P ⁇ 0.001) but not in eNHR3.1 mice.
  • FIG. 10 depicts experimental data showing that precise and prolonged anterior cingulate cortex (ACC) optogenetic inhibition disrupts remote, but not recent, fear memory recall.
  • FIG. 10A depicts eNpHR3.0 expression in the anterior cingulate cortex (ACC).
  • FIG. 10 depicts experimental data showing that precise and prolonged anterior cingulate cortex (ACC) optogenetic inhibition disrupts remote, but not recent, fear memory recall.
  • FIG. 10A depicts eNpHR3.0 expression in the anterior cingulate cortex (ACC).
  • the present disclosure is believed to be useful for modifying memory function on a temporal basis. Specific applications of the present invention facilitate disrupting memory retrieval and/or emotional responses linked to memory retrieval. As many aspects of the example embodiments disclosed herein relate to and significantly build on previous developments in this field, the following discussion summarizes such previous developments to provide a solid understanding of the foundation and underlying teachings from which implementation details and modifications might be drawn. It is in this context that the following discussion is provided and with the teachings in these references incorporated herein by reference. While the present invention is not necessarily limited to such applications, various aspects of the invention may be appreciated through a discussion of various examples using this context.
  • Control over the neural circuit can include inhibition or excitation, which can each include coordinated firing, and/or modified susceptibility to external circuit inputs.
  • inhibition can be accomplished using a light-activated protein, such as an ion channel and/or ionic pump (e.g., NpHR and NpHR variants).
  • ion channels move the membrane potential of the neuron away from its threshold voltage to dissuade or inhibit action potentials.
  • excitation can be accomplished using a light-activated protein, such as an ion channel (e.g., ChR2 and ChR2 variants).
  • ion channels can cause the membrane potential to move toward and/or past the threshold voltage, thereby exciting or encouraging action potentials.
  • a light-activated protein can be used to (temporarily) shift the resting potential of a neuron to increase or decrease its susceptibility to external circuit inputs.
  • the devices and methods provided herein may reversibly affect memory function.
  • the methods described below may be used to control and/or characterize the neural circuitry that underlies long-term and short-term memory, as well as various types of memories, including fearful or stressful memories.
  • the methods may also affect various stages of memory function (e.g., memory acquisition, consolidation, and recall).
  • memory function is affected by applying light to neurons of the dorsal CA1 region of the hippocampus, in the basolateral amygdala (BLA), and/or in the anterior cingulated cortex (ACC) that express light-activated proteins.
  • BLA basolateral amygdala
  • ACC anterior cingulated cortex
  • these light-activated proteins may inhibit depolarization of the neurons, thereby disturbing the formation and/or retrieval of memories. While the exemplary methods are described in the context of the acquisition and recall of contextual remote and recent fear-based memories, it should be understood that the devices and methods disclosed herein may be used to affect other stages of memory function, as well as other types of memories (e.g., cued memories).
  • neuronal activity may be affected using a variety of mechanisms. Deterministic methods of affecting neuronal activity may be used to control and/or characterize the neural circuits that underlie various brain functions. For example, neuronal responses may be affected by applying pharmacological agents (e.g., tetrodotoxin (TTX), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), picrotoxin, strychnine, etc.) and/or by electrical stimulation (e.g., electrodes). In some variations, neuronal activity may be affected by activating certain types of proteins on the membrane of the neuron, which may hyperpolarize or depolarize the cell membrane.
  • pharmacological agents e.g., tetrodotoxin (TTX), 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX), picrotoxin, strychnine, etc.
  • electrical stimulation e.g., electrodes
  • neuronal activity may be affected by activating certain
  • light-activated proteins that become permeable to certain ions (e.g., cations, anions) in the presence of light with a certain wavelength may be expressed in a neuron.
  • ions e.g., cations, anions
  • Examples of light-activated proteins may include light-activated ion channels and/or pumps, which are further described below.
  • microbial opsin genes may be adapted for uses in neuroscience. These opsins allow transduction of light pulse trains into millisecond-timescale membrane potential changes in specific cell types within the intact mammalian brain (e.g., channelrhodopsin (ChR2), Volvox channelrhodopsin (VChR1) and halorhodopsin (NpHR)).
  • ChR2 is a rhodopsin derived from the unicellular green alga Chlamydomonas reinhardtii.
  • the term “rhodopsin” as used herein is a protein that comprises at least two building blocks, an opsin protein, and a covalently bound cofactor, usually retinal (retinaldehyde).
  • the rhodopsin ChR2 is derived from the opsin Channelopsin-2 (Chop2), originally named Chlamyopsin-4 (Cop4) in the Chlamydomonas genome.
  • Chop2 opsin Channelopsin-2
  • Cop4 Chlamyopsin-4
  • the temporal properties of one depolarizing channelrhodopsin, ChR2 include fast kinetics of activation and deactivation, affording generation of precisely timed action potential trains.
  • the normally fast off-kinetics of the channelrhodopsins can be slowed.
  • certain implementations of channelrhodopsins apply 1 mW/mm 2 light for virtually the entire time in which depolarization is desired, which can be less than desirable.
  • Light-activated proteins that generate hyperpolarization or inhibit depolarization of the membrane in response to light with certain wavelength(s) may be expressed in the excitatory neurons (e.g., glutamatergic neurons) of the dorsal CA1 region of the hippocampus (CA1), basolateral amygdala (BLA), and anterior cingulated cortex (ACC) regions.
  • Table 1 below shows various examples of light-activated proteins that may be expressed in the excitatory neurons to inhibit depolarization or hyperpolarize the neurons in the presence of light of a certain wavelength. Further description of these and other light-activated proteins may be found in PCT App. No. PCT/US11/028893, titled “LIGHT SENSITIVE ION PASSING MOLECULES”, filed on Mar. 17, 2011, which is incorporated by reference in its entirety.
  • NpHR”, “BR”, “AR”, and “GtR3” include wild type proteins and functional variants (including naturally occurring variants).
  • Embodiments of the present invention include relatively minor amino acid variants of the naturally occurring sequences.
  • the variants are greater than about 75% homologous to the protein sequence of the naturally occurring sequences.
  • the homology is greater than about 80%.
  • Yet other variants have homology greater than about 85%, greater than 90%, or even as high as about 93% to about 95% or about 98%.
  • Homology in this context means sequence similarity or identity, with identity being preferred. This homology can be determined using standard techniques known in the field of sequence analysis.
  • compositions of embodiments of the present invention include the protein and nucleic acid sequences provided herein, including variants which are more than about 50% homologous to the provided sequence, more than about 55% homologous to the provided sequence, more than about 60% homologous to the provided sequence, more than about 65% homologous to the provided sequence, more than about 70% homologous to the provided sequence, more than about 75% homologous to the provided sequence, more than about 80% homologous to the provided sequence, more than about 85% homologous to the provided sequence, more than about 90% homologous to the provided sequence, or more than about 95% homologous to the provided sequence.
  • non-human animals comprising a light-activated protein expressed on the cell membrane of excitatory neurons in the dorsal CA1 field of the hippocampus, anterior cingulated cortex, and/or basolateral amygdala of the animal, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, wherein the illumination of the protein reversibly affects memory function.
  • the light-activated protein is selected from the group consisting of NpHR, BR, AR and GtR3 described herein.
  • any of the NpHR proteins described herein may be expressed on the cell membrane of the target neurons.
  • brain tissue slices comprising a brain region selected from the group consisting of the dorsal CA1 field of the hippocampus, the basolateral amygdala, and the anterior cingulated cortex, wherein a light-activated protein is expressed on the cell membrane of excitatory neurons of the brain region, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, wherein the illumination of the protein reversibly affects memory function.
  • the brain tissue slices are cultured tissue slices taken from the non-human animals described herein.
  • the light-activated protein is selected from the group consisting of NpHR, BR, AR and GtR3 described herein. For example, any of the NpHR proteins described herein may be expressed on the cell membrane of the target neurons.
  • neurons of the CA1, BLA, and/or ACC regions may express ChR2.
  • the invention includes a number of similar variants. Examples include, but are not limited to, Chop2, ChR2-310, Chop2-310, and Volvox channelrhodopsin (VChR1).
  • VChR1 Volvox channelrhodopsin
  • similar modifications can be made to other opsin or light-activated molecules. For instance, modifications/mutations can be made to ChR2 or VChR1 variants.
  • the modified variants can be used in combination with light-activated ion pumps.
  • stimulation of a target cell is generally used to describe modification of properties of the cell.
  • the stimulus of a target cell may result in a change in the properties of the cell membrane that can lead to the depolarization or polarization of the target cell.
  • the target cell is a neuron and the stimulus may affect the transmission of impulses by facilitating or inhibiting the generation of impulses (action potentials) by the neuron.
  • Embodiments of the present disclosure are directed toward implementation of bistable changes in the excitability of targeted populations.
  • This includes, but is not necessarily limited to, the double-mutant ChR2-C128S/D156A.
  • This double-mutant ChR2-C128S/D156A has been found to be well-tolerated in cultured hippocampal neurons and preserved the essential SFO properties of rapid step-like activation with single brief pulses of blue light, and deactivation with green or yellow light.
  • the activation spectrum of ChR2-C128S/D156A peaks at 445 nm.
  • a second deactivation peak was found at 390-400 nm, with faster but less complete deactivation by comparison with the 590 nm deactivation peak.
  • the double-mutant gene is referred to as SSFO (for stabilized step-function opsin) gene.
  • SSFO is also used as shorthand for the active protein. Both residues likely are involved in ChR2 channel closure (gating), and both mutations likely stabilize the open state configuration of the channel
  • aspects of the present disclosure relate to the discovery that SSFO may be completely blocked in photocycle progression, and may therefore represent the maximal stability possible with photocycle engineering. For instance, in contrast to ChR2 C128X and ChR2-D156A, the SSFO photocycle does not appear to access additional inactive deprotonated side products which likely split off the photocycle at later photocycle stages not reached in this mutant, in turn making the SSFO even more reliable for repeated use in vivo than the parental single mutations.
  • Embodiments of the present disclosure are directed toward the sensitivity of the SSFO to light. For instance, channelrhodopsins with slow decay constants effectively act as photon integrators. This can be particularly useful for more-sensitive, less-invasive approaches to optogenetic circuit modulation, still with readily titratable action on the target neuronal population via modulation of light pulse length. It has been discovered that, even at extraordinarily low light intensities (as low as 8 ⁇ W mm ⁇ 2 ), hundreds of picoamps of whole-cell photocurrents could be obtained from neurons expressing SSFO, which increased with monoexponential kinetics in response to 470 nm light during the entire time of illumination.
  • activation time constants that are linearly correlated with the activation light power on a log-log scale, which is indicative of a power-law relationship and suggesting that the SSFO is a pure integrator, with total photon exposure over time as the only determinant of photocurrent. For instance, it is believed that the number of photons per membrane area required for photocurrents to reach a given sub-maximal activation (time to ⁇ ) is constant regardless of activation light power.
  • Example embodiments of the present disclosure relate to the use of a hybrid ChRI/VChRI chimera, which contains no ChR2 sequence at all and is derived from two opsins genes that do not express well individually, and is herein referred to as C1V1.
  • Embodiments of the present disclosure also relate to improvements of the membrane targeting of VChR1 through the addition of a membrane trafficking signal derived from the K ir 2.1 channel. Confocal images from cultured neurons expressing VChR1-EYFP revealed a large proportion of intracellular protein compared with ChR2; therefore, to improve the membrane targeting of VChR1, we added a membrane trafficking signal derived from the Kir2.1 channel.
  • VChR1-ts-EYFP Membrane targeting of this VChR1-ts-EYFP was slightly enhanced compared with VChR1-EYFP; however, mean photocurrents recorded from cultured hippocampal neurons expressing VChR1-ts-EYFP were only slightly larger than those of VChR1-EYFP. Accordingly, embodiments of the present disclosure relate VChR1 that is modified by exchanging helices with corresponding helices from other ChR5. For example, robust improvement has been discovered in two chimeras where helices 1 and 2 were replaced with the homologous segments from ChR1.
  • ChR1V1 ChR1/VChR1 chimera
  • C1V1-EYFP exhibits surprisingly improved average fluorescence compared with VChR1-EYFP.
  • Whole cell photocurrents in neurons expressing C1V1 were much larger than those of VChR1-EYFP and VChR1-ts-EYFP, and ionic selectivity was similar to that of ChR2 and VChR1.
  • the addition of the Kir2.1 trafficking signal between C1V1 and YFP further enhanced photocurrents by an additional 41%.
  • C1V1-ts-EYFP mean photocurrents were extremely large, nearly tenfold greater than wild type (WT) VChR1).
  • Mean fluorescence levels closely matched the measured photocurrents (mean fluorescence 9.3 ⁇ 1, 19.6 ⁇ 3.4, 19.8 ⁇ 2.8 and 36.3 ⁇ 3.8 for VChR1-EYFP, VChR1-ts-EYFP, C1V1-EYFP and C1V1-ts-EYFP, respectively), suggesting that the increase in photocurrent sizes resulted mainly from the improved expression of these channels in mammalian neurons.
  • opsins or light-activated proteins with fast decay constants. This property can be particularly useful for providing precise control over spiking, e.g., in order to interfere minimally with intrinsic conductances, trigger single spikes per light pulse and/or minimize plateau potentials during light pulse trains.
  • Experimental results suggest that the light-evoked photocurrents recorded in C1V1-ts-EYFP decayed with a time constant similar to that of VChR1.
  • aspects of the present disclosure are therefore directed toward modifications in the chromophore region to improve photocycle kinetics, reduced inactivation and/or possible further red-shifted absorption.
  • ChETA mutation E162T is directed toward a corresponding ChETA mutation E162T, which experiments suggest provides an accelerated photocycle (e.g., almost 3-fold), (reference can be made to Gunaydin, et al., Ultrafast optogenetic control, Nat Neurosci, 2010, which is fully incorporated herein by reference). Surprisingly, this mutation was shown to shift the action spectrum hypsochromic to 530 nm, whereas analogous mutations in ChR2 or other microbial rhodopsins have caused a red-shift.
  • C1V1-E122T Another embodiment is directed toward a mutation of glutamate-122 to threonine (C1V1-E122T).
  • Experimental tests showed that C1V1-E122T is inactivated only by 26% compared to 46% inactivation of ChR2; in addition, the spectrum was further red-shifted to 546 nm.
  • Another embodiment of the present disclosure is directed toward a double mutant of C1V1 including both E122T and E162T mutations.
  • Experimental tests have shown that the inactivation of the current was even lower than in the E122T mutant and the photocycle was faster compared to E162T. This suggests that multiple useful properties of the individual mutations were conserved together in the double mutant.
  • Light-activated proteins or opsins described herein may be delivered into neurons by methods known in the art, such as by a polynucleotide comprising a sequence encoding the proteins.
  • the polynucleotide comprises an expression cassette.
  • the polynucleotide is a vector, such as a viral vector selected from the group consisting of an AAV vector, a retroviral vector, an adenoviral vector, an HSV vector, and a lentiviral vector.
  • neurons may be contacted with a vector comprising a nucleic acid sequence encoding a light-activated protein operably linked to a cell specific promoter, wherein said neurons express the light-activated protein on the cell membrane.
  • the cell specific promoter is a calcium/calmodulin-dependent protein kinase Ha (CaMKIIa) promoter.
  • a nucleic acid sequence encoding light activatable eNpHR3.1 or eNpHR3.0 is operably linked to a CaMKIIa promoter in the vector.
  • the light-activated protein is expressed in excitatory glutamatergic neuron in the CA1 region, BLA and/or ACC. Any vectors that may be used for gene delivery may be used.
  • a viral vector such as AAV, adenovirus, lentivirus, a retrovirus may be used.
  • the vector is a recombinant AAV vector.
  • AAV vectors are DNA viruses of relatively small size that can integrate, in a stable and sitespecific manner, into the genome of the cells that they infect. They are able to infect a wide spectrum of cells without inducing any effects on cellular growth, morphology or differentiation, and they do not appear to be involved in human pathologies.
  • the AAV genome has been cloned, sequenced and characterized. It encompasses approximately 4700 bases and contains an inverted terminal repeat (ITR) region of approximately 145 bases at each end, which serves as an origin of replication for the virus.
  • ITR inverted terminal repeat
  • the remainder of the genome is divided into two essential regions that carry the encapsidation functions: the left-hand part of the genome, that contains the rep gene involved in viral replication and expression of the viral genes; and the right-hand part of the genome, that contains the cap gene encoding the capsid proteins of the virus.
  • AAV vectors may be prepared using standard methods in the art.
  • Adeno-associated viruses of any serotype are suitable (see, e.g., Blacklow, pp. 165-174 of “ Parvoviruses and Human Disease” J. R. Pattison, ed. (1988); Rose, Comprehensive Virology 3:1, 1974; P. Tattersall “The Evolution of Parvovirus Taxonomy” In Parvoviruses (J R Kerr, S F Cotmore. M E Bloom, R M Linden, C R Parrish, Eds.) p 5-14, Hudder Arnold, London, UK (2006); and D E Bowles, J E Rabinowitz, R J Samulski “ The Genus Dependovirus ” (J R Kerr, S F Cotmore.
  • the replication defective recombinant AAVs according to the invention can be prepared by co-transfecting a plasmid containing the nucleic acid sequence of interest flanked by two AAV inverted terminal repeat (ITR) regions, and a plasmid carrying the AAV encapsidation genes (rep and cap genes), into a cell line that is infected with a human helper virus (for example an adenovirus).
  • ITR inverted terminal repeat
  • rep and cap genes AAV encapsidation genes
  • the vector(s) for use in the methods of the invention are encapsidated into a virus particle (e.g. AAV virus particle including, but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV14, AAV15, and AAV16).
  • a virus particle e.g. AAV virus particle including, but not limited to, AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, AAV13, AAV14, AAV15, and AAV16.
  • the invention includes a recombinant virus particle (recombinant because it contains a recombinant polynucleotide) comprising any of the vectors described herein. Methods of producing such particles are known in the art and are described in U.S. Pat. No. 6,596,53
  • one or more vectors may be administered to neural cells, heart cells, or stem cells. If more than one vector is used, it is understood that they may be administered at the same or at different times to the animal cells.
  • C1V1 opsin genes in neurons were carried out by generating lentiviral vectors encoding C1V1-ts-EYFP and various point mutation combinations discussed herein. The opsins were then expressed in cultured hippocampal neurons and recorded whole-cell photocurrents under identical stimulation conditions (2 ms pulses, 542 nm light, 5.5 mW/mm 2 ). Photocurrents in cells expressing C1V1, C1V1-E162T and C1V1-E122T/E162T were all robust and trended larger than the photocurrents of ChR2-H134R.
  • the experiments also included a comparison of integrated somatic YFP fluorescence and photocurrents from cells expressing C1V1-E122T/E162T and from cells expressing ChR2-H134R.
  • C1V1-E122T/E162T cells showed stronger photocurrents than ChR2-H134R cells at equivalent fluorescence levels. This suggests that C1V1 could possess a higher unitary conductance compared with ChR2-H134R.
  • the test results suggest that the kinetics of C1V1-E122T were slower than those of C1V1-E122T/E162T and that cells expressing C1V1-E122T responded more strongly to red light (630 nm) than cells expressing the double mutant. This can be particularly useful for generating optogenetic spiking in response to red light.
  • inhibitory and/or excitatory neurons residing within the same microcircuit are be targeted with the introduction of various light-activated proteins (e.g., opsins).
  • Experimental tests were performed by separately expressed C1V1-E122T/E162T and ChR2-H134R under the CaMKIIa promoter in cultured hippocampal neurons.
  • Cells expressing C1V1-E122T/E162T spiked in response to 2 ms green light pulses (560 nm) but not to violet light pulses (405 nm).
  • Various embodiments of the present disclosure relate to independent activation of two neuronal populations within living brain slices. Experimental tests were performed by CaMKIIa-C1V1-E122T/E162Tts-eYFP and EF1a-DIO-ChR2-H134R-EYFP in mPFC of 20 PV::Cre mice. In non-expressing PYR cells, 405 nm light pulses triggered robust and fast inhibitory postsynaptic currents (IPSCs) due to direct activation of PV cells, while 561 nm light pulses triggered only the expected long-latency polysynaptic IPSCs arising from C1V1-expressing pyramidal cell drive of local inhibitory neurons.
  • IPCs inhibitory postsynaptic currents
  • any device that is capable of applying light having a wavelength to activate the light-activated proteins expressed in a neuron may be used to depolarize and/or hyperpolarize the neuron.
  • a light-delivery device ( 100 ) for activating ion channels and/or ionic pumps to affect the membrane voltage of one or more neurons depicted in FIG. 1 may be used.
  • the light-delivery device ( 100 ) is configured to provide optical stimulus to a target region of the brain.
  • the light-delivery device ( 100 ) may comprise a base ( 102 ), a cannula guide ( 104 ) that is attached to the base, and one or more optical conduits ( 106 ) attached to the base via the cannula guide.
  • the base ( 102 ) may comprise one or more light delivery ports ( 108 ) that are positioned to deliver light from the optical conduits ( 106 ) to targeted tissue regions ( 101 ), such as the CA1 region ( 103 ).
  • the optical conduits ( 106 ) may be optical fibers, where the proximal end of the fiber is attached to an optical light source (not shown), and the distal end is in communication with the light delivery ports ( 108 ).
  • the optical light source may be capable of providing continuous light and/or pulsed light, and may be programmable to provide light in pre-determined pulse sequences.
  • the light delivery device ( 100 ) may have any number of optical conduits ( 106 ) as may be desirable, e.g., 1, 2, 3, 4, 5, 10, 15, 20, etc.
  • the optical conduits ( 106 ) may each carry light of the same or different wavelengths.
  • the delivered light may have a wavelength between 450 nm and 600 nm, such as yellow or green light.
  • the light delivery device ( 100 ) may have any number of light delivery ports ( 108 ) as may be desirable, e.g., 1, 2, 3, 4, 5, 10, 15, 20, etc. In some variations, there may be the same number of light delivery ports as optical conduits while in other variations, there may be different number of optical conduits and light delivery ports.
  • the cannula guide ( 104 ) may be configured to help secure and align the optical conduits ( 106 ) with the light delivery ports ( 108 ).
  • the light delivery device ( 100 ) is configured to deliver bilateral light to the CA1 region ( 103 ) to affect the formation and retrieval of memories.
  • Light delivery devices may also comprise one or more measurement electrodes that may be configured for measuring neural activity. For example, measurement electrodes may record changes in the membrane potential (e.g., action potentials) and/or current flow across a membrane of one or more neurons as the neurons respond to a stimulus. In some variations, the measurement electrodes may measure the electrical response of one or more neurons to optical stimulation. Measurement electrodes may be extracellular or intracellular electrodes.
  • the target tissue regions ( 101 ) may include neural tissue with cells that have light-activated proteins designed to modify the membrane voltage of the cells in response to light.
  • light-activated proteins may be used to disrupt the formation and/or retrieval of memories by inhibiting the depolarization of the neurons in the CA1, BLA, and ACC regions of the brain.
  • Embodiments of the present disclosure are directed towards disrupting memory acquisition, recall and/or associations between memory and emotional responses, such as fear.
  • function of a neural circuit involved in memory is disrupted by activation of light-activated ion channels (e.g., using NpHR, BR, AR, etc.) and/or pumps (e.g., a proton pump GtR3).
  • this disruption can be implemented during memory formation. In other implementations, this disruption can be implemented before or during memory retrieval. This can be particularly useful for psychiatric or neurological disorders involving memory recall, such as PTSD. Consistent with certain embodiments, the disruption can be triggered in response to a memory trigger event or other external stimulus that is presented and/or controlled for the disruption. For instance, the disruption can be provided in response to a trigger for a memory to an individual conditioned to respond to the trigger. In another instance, an individual can actively trigger the disruption. For instance, an individual may trigger the disruption when experiencing a memory associated with PTSD. Other embodiments of the present disclosure are directed toward encouraging memory acquisition, recall and/or associations between memory and emotional responses. The methods described herein may be used to ascertain the role of neuron(s) and/or neuronal circuits in memory function, and/or to treat disorders associated with memory impairment.
  • the methods provided herein for reversibly affecting memory retrieval or formation in an individual comprise administering a polynucleotide encoding a light-activated protein to the dorsal CA1 field of the hippocampus, anterior cingulated cortex, or basolateral amygdala in the individual, wherein light-activated protein is expressed on the cell membrane of the excitatory neurons in the dorsal CA1 field of the hippocampus, anterior cingulated cortex, or basolateral amygdala and the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, whereby activating the protein by the light reversibly affects memory retrieval or formation of an event in the individual.
  • the methods provided herein for reversibly affecting memory retrieval or formation in an individual comprise inhibiting depolarization of excitatory neurons in the dorsal CA1 field of the hippocampus, anterior cingulated cortex, or basolateral amygdala during memory retrieval or formation of an event in an individual, wherein a light-activated protein is expressed on the cell membrane of the excitatory neurons in the dorsal CA1 field of the hippocampus, anterior cingulated cortex, or basolateral amygdala of the individual, wherein the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light.
  • the event is a fearful event.
  • kits for treating post-traumatic stress disorder in an individual comprising: administering a polynucleotide encoding a light-activated protein to the dorsal CA1 field of the hippocampus, anterior cingulated cortex, or basolateral amygdala in the individual, wherein light-activated protein is expressed on the cell membrane of the excitatory neurons in the dorsal CA1 field of the hippocampus, anterior cingulated cortex, or basolateral amygdala and the protein is responsive to light and is capable of inhibiting depolarization of the neurons when the neurons are illuminated with the light, whereby activating the protein by the light reversibly affects memory retrieval or formation of an event in the individual.
  • an “individual” is a mammal including a human. Mammals include, but are not limited to, farm animals, sport animals, pets, primates, mice and rats. Individuals also include companion animals including, but not limited to, dogs and cats. In one aspect, an individual is a human. In another aspect, an individual is a non-human animal. As used herein, “non-human animals” include non-human mammals.
  • a temporal-trigger event ( 202 ) provides a reference point for implementing control over memory function. As discussed herein, the temporal nature of the control can be particularly useful.
  • the memory-trigger event ( 202 ) can be linked to a training event. For instance, an individual (e.g., non-human animals, mammals, humans) can be introduced to a stimulus designed to train the individual to respond to a particular stimulus. The memory-trigger event ( 202 ) could be the introduction of the particular stimulus to the individual.
  • control instructions ( 204 ) determine how stimulus source ( 206 ) applies a stimulus ( 208 ) to a cell population ( 210 ). These control instructions can be determined and applied as a function of a desired target.
  • the desired target can be defined by, for example, one or more of temporal attributes, spatial location and/or cell-type.
  • the stimulus ( 208 ) results in the modification of memory function ( 212 ). The effect of the stimulus can then be monitored, observed and/or assessed ( 214 ).
  • the monitoring can be used to adjust ( 216 ) the control instructions ( 204 ), thereby fine-tuning the stimulus for the intended result.
  • Various embodiments discussed herein provide further examples that can be used in connection with (or in addition to) such a process for controlling and characterizing the neural circuits that underlie memory function.
  • One variation of a method for disrupting memory retrieval may comprise inhibiting the excitatory neurons of the CA1 region (e.g., by blocking or reducing membrane depolarization, and/or by promoting membrane hyperpolarization).
  • Light-activated ion channels such as eNpHR3.1 or NpHR3.0, may be expressed on neurons located in the CA1 region of an individual by administering a polynucleotide encoding the channel protein to the region.
  • the eNpHR3.1 or NpHR3.0 ion channel is activated in the presence of yellow light (e.g., having a wavelength of about 591 nm).
  • the individual may be provided with a light-delivery device, such as the light-delivery device ( 100 ) described above.
  • the light-delivery device may be positioned on the individual such that yellow light is capable of being delivered to the CA1 neurons.
  • a memory e.g., any undesired memory such as a fearful or stressful memory
  • the light-delivery device may be activated to deliver yellow light to the CA1 neurons, thereby inhibiting their depolarization, and disrupting the recall of the memory. Once the memory recall has been sufficiently disrupted, the light-delivery device may be de-activated. Upon de-activation of the light-delivery device, the individual may regain the ability retrieve memories without disruption.
  • This method may be used to disrupt recall of recent memories (e.g., memories of events that occurred less than one day in the past) and recall of remote memories (e.g., memories of events that occurred more than one day in the past, 1 week in the past, 2 weeks in the past, 4 weeks in the past, 8 weeks or more in the past, etc.).
  • excitatory neurons of the ACC may express similar light-activated proteins, and may be similarly inhibited to disrupt the retrieval of remote memories.
  • Methods for disrupting memory retrieval comprising inhibiting the neurons of the CA1 region may be used in a non-human animal, such as a mouse.
  • a non-human animal such as a mouse.
  • mice expressing eNpHR3.1 or NpHR3.0 in the neurons of the CA1 region were trained in a customized FC chamber, where they were introduced into context A and then presented twice with a tone followed by a foot-shock.
  • green light delivered to the eNpHR3.1 or NpHR3.0 CA1 neurons interfered with the ability of the mice to recall the memory (i.e., a fearful or stressful memory), as measured by a reduction in freezing (e.g., contextual freezing).
  • the mice are able to recall the fearful memory formed during the training session, as measured by normal rates of freezing.
  • the testing session may occur one day or less after the training session, while in other variations, the testing session may occur four weeks or more after the training session.
  • Applying green light to the eNpHR3.1 CA1 neurons of the mice reversibly inhibits the depolarization of the neurons, thereby disrupting the recall of recent and/or remote contextual fearful memories. Removing the green light from the eNpHR3.1 or NpHR3.0 CA1 neurons restores the ability of the mice to recall recent and/or remote contextual fearful memories.
  • mice having CA1 neurons expressing eNpHR3.1 or NpHR3.0 may be trained as described above. In a testing session five weeks after the training session, the mice were able to recall the memory formed during training, however, when the eNpHR3.1 or NpHR3.0 CA1 neurons were exposed to green light, they were no longer able to recall the memory. Subsequent exposure of the eNpHR3.1 or NpHR3.0 CA1 neurons to green light disrupted retrieval of the fearful memory.
  • memory recall may be disrupted by exposing the eNpHR3.1 or NpHR3.0 CA1 neurons to light upon initiation of the memory recall and/or during the memory recall. For example, applying green light to the eNpHR3.1 or NpHR3.0 CA1 neurons at the same time as recall initiation (e.g., at the beginning of the testing session) disrupts recall of the memory.
  • green light was applied to the eNpHR3.1 or NpHR3.0 CA1 neurons during memory recall (e.g., applying the light some time after the testing session has begun, such as in the middle of the testing session), the mice initially recalled and responded to the fearful memory (by freezing), but then quickly ceased exhibiting the fear response after the light was applied.
  • a light-delivery device may be activated at the same time and/or during the retrieval of a fearful memory in order to reversibly disrupt and/or discontinue recall of that fearful memory. Subsequent de-activation of the light-delivery device may restore the ability of the individual to recall this and other memories.
  • Methods for disrupting memory retrieval comprising inhibiting the neurons of the ACC region may be used in a non-human, such as a mouse.
  • mice expressing eNpHR3.1 in the neurons of the ACC may be trained as described above.
  • green light delivered to the eNpHR3.1 ACC neurons interfered with the ability of the mice to recall the memory formed during training. Removing the green light from the eNpHR3.1 CA1 neurons restores the ability of the mice to remote fearful memories.
  • One variation of a method for disrupting memory formation may comprise inhibiting the neurons of the CA1 region during the formation of a memory such as a contextual memory.
  • Light-activated ion channels such as eNpHR3.1, may be expressed on neurons located in the CA1 region of an individual as previously described.
  • the individual may be provided with a light-delivery device, such as the light-delivery device ( 100 ) described herein.
  • the light-delivery device may be activated to deliver green light to the CA1 neurons, thereby inhibiting their depolarization and disrupting the formation of the memory. Once the memory formation has been sufficiently disrupted, the light-delivery device may be de-activated. Upon de-activation of the light-delivery device, the individual may regain the ability form memories without disruption.
  • a memory e.g., a fearful or stressful memory
  • Methods for disrupting memory formation comprising inhibiting the neurons of the CA1 region may be used in a non-human animal, such as a mouse.
  • a non-human animal such as a mouse.
  • mice expressing eNpHR3.1 in the neurons of the CA1 region were trained in a customized FC chamber, while delivering green light to the eNpHR3.1 CA1 neurons.
  • the mice were introduced into a first context and then exposed to a tone followed by a foot-shock.
  • the mice exhibited no memory of the training, as measured by a reduction in contextual freezing.
  • the same mice underwent a separate training session where the eNpHR3.1 CA1 neurons were not exposed to light. The mice were then able to recall the memory in a subsequent testing session.
  • the testing session may occur one day or less after the training session, while in other variations, the testing session may occur four weeks after the training session.
  • Applying green light to the eNpHR3.1 CA1 neurons of the mice reversibly inhibited the depolarization of the neurons, thereby disrupting the formation of recent and/or remote memories. Removing the green light from the eNpHR3.1 CA1 neurons restored the ability of the mice to form fearful memories.
  • Some variations of methods for disrupting memory formation may comprise delivering light to neurons expressing eNpHR3.1 in the BLA during memory formation.
  • Light-activated ion channels such as eNpHR3.1, may be expressed on neurons located in the BLA of an individual.
  • the individual may be provided with a light-delivery device, such as the light-delivery device ( 100 ) described above.
  • the light-delivery device may be positioned on the individual such that green light is capable of being delivered to the BLA neurons.
  • a memory e.g., a fearful or stressful memory
  • the light-delivery device may be activated to deliver green light to the BLA neurons, thereby inhibiting their depolarization, and disrupting the formation of the memory.
  • the light-delivery device may be de-activated. Upon de-activation of the light-delivery device, the individual may regain the ability acquire memories without disruption.
  • Methods for disrupting memory acquisition comprising inhibiting the neurons of the BLA region may be used in a non-human animal, such as a mouse.
  • a non-human animal such as a mouse.
  • green light may be delivered to mice expressing eNpHR3.1 in the neurons of the BLA during a fear conditioning training session as described above. The mice may then be tested to determine whether they acquired the fearful memory of the training session. Green light delivered to the BLA during the training session may disrupt the ability of the mice to acquire a fearful or stressful memory.
  • Controlling the neural circuit that underlies memory function may provide a tool for evaluating the effect of pharmacological agents on memory retrieval. For example, inhibiting the neurons expressing eNpHR3.1 of the CA1 region and/or ACC and/or BLA may be used to evaluate the effectiveness of various pharmacological agents for the restoration of memory recall.
  • FIG. 3A One example of a method for identifying a pharmacological agent that activates depolarization or excitation of non-human excitatory neurons in the CA1 region and/or ACC and/or BLA is depicted in FIG. 3A .
  • the method ( 300 ) may comprise delivering a light-activated protein to the CA1 region and/or ACC and/or BLA of the brain ( 302 ) and inhibiting depolarization of excitatory neurons of the CA1 and/or ACC region ( 303 ).
  • inhibiting depolarization may comprise applying light having a selected wavelength (e.g., yellow or green) to eNpHR3.1 ion channels expressed on the neurons of the CA1 and/or ACC region to prevent the generation of action potentials.
  • Other types of light-activated channels may also be expressed to inhibit depolarization of these excitatory cells, such as variants of NpHR, BR, AR, and proton pumps such as GtR3.
  • the effect of the inhibition from activating the eNpHR3.1 ion channels may be electrically measured by using loose-cell or whole-cell patch clamp methods ( 304 ).
  • the electrical activity of the excitatory cells of the CA1 and/or ACC region may be measured using single electrodes and/or multielectrode arrays.
  • the inhibited neurons of the CA1 and/or ACC region may then be contacted with a test pharmacological agent ( 306 ).
  • the electrical activity of the neurons may be similarly measured ( 308 ).
  • the electrical measurements of the excitatory neurons of the CA1 region and/or ACC and/or BLA before and after contacting with the test pharmacological agent may be compared to determine if the test agent activates and/or restores the depolarization of the neurons ( 310 ).
  • the method ( 300 ) may be used repeatedly as desired to screen any number or variety of pharmacological agents.
  • the method ( 320 ) may comprise delivering a light-activated protein to the CA1 region and/or ACC and/or BLA of the brain ( 322 ) and applying light have a selected wavelength (e.g., yellow or green) to eNpHR3.1 ion channels expressed on the neurons of the CA1 and/or ACC and/or BLA region to prevent the generation of action potentials ( 323 ).
  • a selected wavelength e.g., yellow or green
  • the response of the non-human animal in the presence of the light during memory formation or retrieval may be measured ( 324 ).
  • the memory may be formed during a training session where the individual is introduced into context A and exposed to a tone accompanied by a foot-shock, and the response to memory retrieval may be freezing when introduced into the context A and/or when the tone is played.
  • the inhibited neurons of the CA1 and/or ACC region may then be contacted with a test pharmacological agent ( 326 ).
  • the response of the non-human animal may be similarly measured ( 328 ).
  • the response of the non-human animal before and after contacting with the test pharmacological agent may be evaluated to determine if the test agent affects memory formation or retrieval in the presence of light ( 330 ).
  • the method ( 320 ) may be used during memory formation (e.g., a training session) to evaluate the effect of the pharmacological agent on memory formation.
  • the method ( 320 ) may also be used during memory retrieval (e.g., a testing session some time after a training session) to evaluate the effect of the pharmacological agent on memory retrieval.
  • the method ( 320 ) may be used repeatedly as desired to screen any number or variety of pharmacological agents.
  • inhibition of the neurons expressing the light-activated protein may be applied at a precise point in time.
  • neurons expressing eNpHR3.1 in the CA1 region may illuminated by light during the testing session only.
  • Temporally precise inhibition of neurons expressing eNpHR3.1 may disrupt memory recall.
  • Precisely applying light to neurons expressing eNpHR3.1 in the CA1 region of mice during the testing session may inhibit remote and/or recent fear memory retrieval in an animal.
  • inhibition of the neurons expressing eNpHR3.1 may be applied over a prolonged period of time.
  • neurons expressing eNpHR3.1 in the CA1 region may be illuminated by light before the testing session (e.g., 30 minutes or more before the testing session).
  • Prolonged inhibition of the neurons expressing eNpHR3.1 in the CA1 region of the hippocampus may affect the retrieval of memories differently from precise inhibition of the CA1 neurons.
  • prolonged light application (i.e., prolonged inhibition) to CA1 neurons may affect recent contextual fear recall, but may not affect remote contextual memory recall.
  • a method for treating PTSD may comprise administering a viral vector encoding a light-activated protein to an individual.
  • the light-activated protein may be configured to inhibit depolarization of the neuron in the presence of light with a specific wavelength. Examples of such light-activated proteins may include NpHR, BR, AR, and GrR3.
  • the viral vector may be delivered to any neuron population or type (e.g., the excitatory neurons of the CA1, ACC, and BLA brain regions).
  • the neuron(s) expressing the light-activated protein may be inhibited from depolarizing, thereby disrupting the retrieval of the undesired memory.
  • inhibiting depolarization of the neuron(s) may comprise applying light of the specific wavelength to the neurons expressing the light-activated proteins.
  • the light may be removed. This may restore memory function such that memories may be recalled without disruption.
  • memories related to drugs of abuse can be inhibited to reduce drug-seeking behavior.
  • Other embodiments are directed toward the ability to instantaneously affect cognition by modulation of different brain areas in order to study the role of specific neuronal populations in memory processes. Inhibition of neurons by certain light-activated proteins and activation by other light-activated proteins may enable a finer temporal, genetic and spatial dissection of the neuronal circuits that underlie various brain function and behaviors.
  • the method comprising: inhibiting the function of the dorsal CA1 hippocampus circuit with a temporal precision of the inhibition that is sufficient to disrupt the effects of remote memory retrieval.
  • the step of inhibiting is responsive to a memory trigger event.
  • the step of inhibiting includes activating light-responsive opsins expressed in cells of the dorsal CA1 hippocampus circuit.
  • the step of inhibiting includes applying an electrical pulse through one or more electrodes positioned near the dorsal CA1 hippocampus circuit.
  • the step of inhibiting includes releasing a drug at a location proximate to the dorsal CA1 hippocampus circuit.
  • the effects of remote memory retrieval include emotional responses to a remote memory.
  • Also provided herein are methods of disrupting memory creation comprising: inhibiting the function of the dorsal CA1 hippocampus circuit with a temporal precision of the inhibition that is sufficient to disrupt remote memory creation.
  • the step of inhibiting is responsive to a memory trigger event.
  • the step of inhibiting includes activating light-responsive opsins expressed in cells of the dorsal CA1 hippocampus circuit.
  • the step of inhibiting includes applying an electrical pulse through one or more electrodes positioned near the dorsal CA1 hippocampus circuit.
  • the step of inhibiting includes releasing a drug at a location proximate to the dorsal CA1 hippocampus circuit.
  • the effects of remote memory retrieval include emotional responses to a remote memory.
  • Also provided herein are methods of encouraging memory function comprising: exciting the function of the dorsal CA1 hippocampus circuit to promote remote memory creation or remote memory recall.
  • Also provided herein are methods for treatment of a neurological disorder associated with remote memory recall comprising: in response to retrieval of the remote memory, inhibiting the function of the dorsal CA1 hippocampus circuit with a temporal precision of the inhibition that is sufficient to disrupt the effects of the retrieval of the remote memory.
  • Various types of light-activated proteins may be used to control and characterize the neural circuits that underlie memory function.
  • variants of NpHR may be used to inhibit depolarization and/or hyperpolarize a neuron.
  • the third generation eNpHR has a trafficking signal between the gene and the fluorophore and has shown improved membrane targeting and increased light-induced hyperpolarizations. This third generation eNpHR was used to perturb the neurons in the CA1 region of the hippocampus to determine their role in both recent and remote memory acquisition and recall.
  • eNpHR3.1 fused in-frame to enhanced yellow fluorescent protein (eNpHR3.1-EYFP) under control of the calcium/calmodulin-dependent protein kinase II ⁇ (CaMKII ⁇ ) promoter, selective for excitatory glutamatergic neurons in hippocampus was used.
  • eNpHR3.1 is a truncated version of eNpHR3.0 with a deletion of the intrinsic N-terminal signal peptide that is similar to eNpHR3.0 in both the photocurrent and the hyperpolarization induced in neurons.
  • mice C57BL6 mice aged 6 to 8 weeks were obtained from Charles River. Mice were housed four to five per cage in a colony maintained on a reversed 12 hr light/dark cycle and given food and water ad libitum. Experimental protocols were approved by Stanford University IACUC and meet guidelines of the National Institutes of Health guide for the Care and Use of Laboratory Animals.
  • the CaMKII ⁇ -eNpHR3.1-EYFP lentivirus for in vivo injection was produced as previously described (Gradinaru et al., 2010; Zhang et al., 2007).
  • the adeno-associated virus (AAV) CaMKII ⁇ -eNpHR3.0-EYFP plasmid was constructed by cloning eNpHR3.0-EYFP into an AAV backbone carrying the CaMKII ⁇ promoter using BamHI and EcoRI restriction sites.
  • the recombinant AAV vectors were serotyped with AAV5 coat proteins and packaged by the Vector Core at the University of North Carolina; titers were 2 ⁇ 1012 particles/mL.
  • the maps for AAV CaMKII ⁇ ::eNpHR3.0 and Lenti CaMKII ⁇ ::eNpHR3.1 are available online at www.optogenetics.org.
  • mice were anesthetized with isoflurane, the head was placed in a stereotactic apparatus (Kopf Instruments, Tujunga, Calif.; Leica stereomicroscope). Ophthalmic ointment was applied to prevent eye drying. A midline scalp incision was made and then a small craniotomy was performed and the virus was delivered using a 101 syringe and a thin 34 gauge metal needle (World Precision Instruments, Sarasota, Fla.). The injection volume and flow rate (1 ⁇ l at 0.1 ⁇ l/min) were controlled by an injection pump (WPI). After injection the needle was left in place for 5 additional minutes and then slowly withdrawn.
  • WPI injection pump
  • a bilateral guide cannula (2.5 mm center to center; PlasticsOne, Roanoke, Va.) was then placed 0.5 mm above CA1 (AP, ⁇ 1.94 mm, ML, +1.25 mm, DV ⁇ 1 mm), and secured to the skull using dental cement (C&B metabond, Parkell, Edgwood, N.Y.). The skin was glued back with Vetbond tissue adhesive. The animal was kept on a heating pad until it recovered from anesthetic. Buprenorphine (0.03 mg/kg) was given subcutaneously at the beginning of the surgical procedure to minimize discomfort.
  • mice To inhibit neuronal activity, green light (561 nm, describe laser etc) was bilaterally delivered through two 300 m thick optic fibers (Thorlabs, Newton, N.J.) that were inserted through the guide cannulas, with a 0.5 mm projection.
  • Control mice were either uninfected with eNpHR3.1 but still implanted with the cannula delivering light into CA1, or were infected with eNpHR3.1 and implanted, but connected to a dummy fiber that terminated the light delivery at the surface of the brain. Control mice therefore experienced identical visual cues and contextual information as the experimental mice associated with laser light delivery.
  • BLA basolateral amygdala
  • 1.5 ⁇ l of AAV5 CaMKII ⁇ ::eNpHR3.0-EYFP was microinjected into both left and right BLA (AP, ⁇ 1.5 mm, ML, ⁇ 3.47 mm, DV ⁇ 5 mm).
  • a patchcord (a metal ferrule, 2.5 mm in diameter with a 200 m thick, 5 mm long, cleaved bare optic fiber; Doric lenses Inc., Quebec, Canada) was then placed in each BLA (AP, ⁇ 1.5 mm, ML, ⁇ 3.47 mm, DV ⁇ 4.8 mm), and secured to the skull using dental cement.
  • Green light was bilaterally delivered through two 200 m thick optic fibers (Doric lenses) that were attached to the patchcord using a connecting plastic sleeve.
  • Doric lenses anterior cingulate cortex
  • ACC anterior cingulate cortex
  • AP anterior cingulate cortex
  • ML anterior cingulate cortex
  • DV DV ⁇ 2.2 mm
  • a patchcord Doric lenses Inc.
  • Green light was delivered through a 200 ⁇ m thick optic fiber (Doric lenses) attached to the patchcord.
  • Doric lenses For olfactory bulb (OB) optogenetic inhibition, 1.0 ⁇ l of AAV5 CaMKII ⁇ ::eNpHR3.0-EYFP was microinjected into both left and right OB (AP, +4.5 mm, ML, ⁇ 0.75 mm, DV ⁇ 3.25 and ⁇ 2 mm).
  • a patchcord Doric lenses Inc.
  • Green light was delivered through a 200 ⁇ m thick optic fiber (Doric lenses) attached to the patchcord.
  • mice were anesthetized with ketamine/xylazine and perfused transcardially with cold PBS followed by 4% paraformaldehyde (PFA) dissolved in phosphate-buffered saline (PBS, pH 7.4).
  • PFA paraformaldehyde
  • the brains were removed and post-fixed in 4% PFA in PBS for 3 hr at 4° C., and then equilibrated in 30% sucrose in PBS.
  • 40 ⁇ m-thick coronal sections were cut on a freezing microtome (Leica) and stored in cryoprotectant (25% glycerol, 30% ethylene glycol, in PBS) at 4° C.
  • Sections were then washed with PBS and incubated for 2 hr at room temperature with secondary antibodies (Donkey anti mouse conjugated to Cy3, donkey anti rabbit conjugated to either Cy3 or Cy5, all 1:1000, Jackson Laboratories, West grove, PA).
  • Slices were then washed, incubated with DAPI (1:50,000) for 20 min, washed again, and mounted on slides with PVA-Dabco (Sigma).
  • Confocal fluorescence images were acquired on a scanning laser microscope using a 5 ⁇ or a 10 ⁇ air objectives, or a 40 ⁇ oil immersion objective. To determine the rate of viral transduction we calculated the percentage of CaMKII ⁇ -immunoreactive neurons per 40 ⁇ field that were also eNpHR-EYFP-positive.
  • the optical fiber was coupled to a 473 nm solid-state laser diode with ⁇ 20 mW of output from the 200 ⁇ m fiber.
  • Single unit recordings were done in mice anesthetized with a ketamine/xylazine mixture (ketamine, 80 mg/kg; xylazine, 15-20 mg/kg) diluted in PBS. Signals were recorded and band-pass filtered at 300 Hz low/5 kHz high using an 1800 Microelectrode AC Amplifier.
  • the fear conditioning apparatus consisted of a square conditioning cage (18 ⁇ 18 ⁇ 30 cm), with a grid floor wired to a shock generator and a scrambler, surrounded by an acoustic chamber (Coulbourn instruments, PA, USA.). The apparatus was modified to enable light delivery during training and/or testing. To induce fear-conditioning mice were placed in the cage for 120 seconds, and then a pure tone (2.9 kHz) was sound for 20 sec, followed by a 2 sec, foot-shock (0.5 mA for short-term memory, 1 mA for long-term memory). This procedure was then repeated, and 30 sec after the delivery of the second shock mice were returned to their home cage.
  • a pure tone 2.9 kHz
  • mice were trained and tested as follows: Day 1—training with continuous 561 nm light administration (light ON). Day 2—contextual and cued tests (2 hr apart) without light administration (light OFF). Day 3—training, light OFF. Day 4—test, light OFF. Day 5—contextual and cued tests, light ON.
  • FIG. 6A Day 1—training, light OFF. Day 29—contextual and cued tests, light ON. Day 30—test light OFF.
  • FIG. 6C Day 1—training, light OFF.
  • Day 64 contextual test, light ON.
  • FIG. 8 Day 1—training, light OFF.
  • Day 36 test, light OFF.
  • Day 37 test light ON.
  • Day 38 test with 3 min light OFF followed by 3 min light ON.
  • mice were trained on day 1 with light ON, and tested for contextual and cued fear on day 2 with light OFF.
  • mice were trained on day 1 with the light OFF, tested on day 2 with the light ON, and then tested on day 29 with light ON.
  • the optic fibers were passed through the conditioning cage into a regular housing cage with bedding, and light was delivered in this cage for 30 min. The mouse was then placed in the conditioning cage for a five min test, as light delivery continued without interruption.
  • the results of the contextual- and cued-conditioning tests were analyzed by a Student's t-test or 2-way ANOVA, followed by post-hoc tests, as applicable.
  • mice were implanted with a double cannula above CA1.
  • the cannula, surgical procedure and location were the same as in the light delivery experiments.
  • TTX Sigma, 20 ⁇ M
  • CNQX Tocris Bioscience, Ellisville, Mo.; 3 mM
  • saline were infused in a volume of 1 ⁇ l through a 28 gauge stainless steel internal cannula (PlasticsOne) that was 0.5 mm longer than the guide cannula.
  • the internal cannula was connected to a micro-syringe pump (Harvard Apparatus, Holliston, Mass.) by a PE20 tube. Solutions were administered at a constant rate of 200 nl/min, and the injection cannula was removed 2 min following the termination of the injection to avoid spillage from the guide cannula.
  • the open field test was conducted in an open plastic arena (50 cm long ⁇ 50 cm wide ⁇ 40 cm deep). Mice were individually placed in the center of the chamber and allowed to freely explore for 3 min. Activity in both the central and periphery of the field was measured using an automated video-tracking system (Biobserve, Bonn, Germany). Percentage of time in center is defined as the percent of total time that was spent in the central 35 ⁇ 35 cm area of the open field.
  • Coronal slices containing dorsal CA1 were prepared by perfusing ice cold sucrose solution transcardially which contained (in mM): 26 NaHCO3, 2.5 KCl, 1.25 NaH2PO4, 10 MgSO4H14O7, 0.5 CaCl2H4O2, 11 glucose, and 234 sucrose, and subsequently cutting 300 micron slices in the same ice cold sucrose solution.
  • Induction of action potentials was done by injecting current ranging from 200 pA at 10 hz.
  • Light for the activation of eNpHR3.1 was delivered using a X-Cite 120 W halogen light source through a 531 ⁇ 20 nm filter and a 40 ⁇ /0.8 NA water objective at 7 mW/mm 2 .
  • Hippocampal Cultures Primary cultured hippocampal neurons were prepared from P0 Sprague-Dawley rat pups. The CA1 and CA3 regions were isolated, digested with 0.4 mg/mL papain (Worthington, Lakewood, N.J.), and plated onto glass coverslips precoated with 1:30 Matrigel (Beckton Dickinson Labware, Bedford, Mass.) at a density of 65,000/cm 2 .
  • DNA/CaCl2 mix for each well: 1.5-3 ⁇ g DNA (QIAGEN endotoxin-free preparation)+1.875 ⁇ l 2M CaCl2 (final Ca2+ concentration 250 mM) in 15 ⁇ l total H20.
  • To DNA/CaCl2 was added 15 ⁇ l of 2 ⁇ HEPES-buffered saline (pH 7.05), and the final volume was mixed well by pipetting.
  • YFP control and eNpHR3.1 mice were trained with light administration during conditioning (without tone presentation, so that only fear of the context would be induced), and sacrificed 90 min later to test for c-Fos levels (described in detail in the immunohistochemistry section above).
  • Two other groups of non-trained control and eNpHR3.1 mice were sacrificed from their home cages.
  • YFP controls and eNpHR3.1 mice were fear-conditioned without light, exposed to the conditioning context with light 28 days later, and sacrificed 90 min afterwards to test for cFos levels.
  • the control groups at this time point were control and eNpHR3.1 mice that were trained, and then sacrificed from their home cages 28 days later without being re-exposed to the conditioning context.
  • eNpHR3.1 is a truncated version of eNpHR3.0 with a deletion of the intrinsic N-terminal signal peptide, that has comparable effects on membrane potential.
  • eNpHR3.1 is targeted to the neuronal membrane, and is expressed around the soma, as well as in the apical and basal dendrites of CA1 neurons ( FIG. 4B ).
  • CA1 Optogenetic Inhibition Blocks Contextual Fear Acquisition and Retrieval.
  • the involvement of the hippocampus in contextual fear conditioning is based on physical, pharmacological and genetic lesions to this structure, in which the interval between lesion and testing ranges from tens of minutes to several weeks (Anagnostaras et al., 1999; Kim and Fanselow, 1992; Kitamura et al., 2009; Shimizu et al., 2000; Wiltgen et al., 2010), which could allow for adaptation and compensation within the relevant neural circuitry.
  • bilateral continuous green (561 nm) light via two optical fibers inserted through a double cannula system was delivered targeting dorsal CA1 ( FIG.
  • mice 5A in freely-moving mice in a customized FC chamber.
  • Light was delivered to all mice, and was accompanied by CA1 inhibition in eNpHR3.1 but not control mice (which were either not infected but implanted with a cannula and received light into CA1, or mice infected and implanted connected to a dummy fiber that did not extend into the brain).
  • mice were introduced into context A, and then presented twice with a tone followed by a foot-shock, under continuous bilateral 561 nm light delivery, and mice were tested for their memory 24 hr later without light.
  • Fear memory was then assessed the next day in the absence of optical inhibition.
  • mice were bilaterally injected in the basolateral amygdala (BLA; FIG. 5H ) instead of hippocampus and it was found that it was possible to optogenetically inhibit both contextual ( FIG. 5I ; 65.5 ⁇ 7.2 vs. 9.6 ⁇ 5.5% freezing; P ⁇ 0.001) and auditory-cued FC acquisition ( FIG. 5I ; 69.5 ⁇ 9.6 vs.
  • the prolonged group mice were re-tested the next day with light during the test only, their recall was disrupted (Prolonged group, left, 55.5 ⁇ 18.5 vs. 27.6 ⁇ 8.6% freezing; P ⁇ 0.05).
  • the same mice were tested under illumination, and the eNpHR3.1 group failed to recall the contextual memory ( FIG. 8 left; 77.2 ⁇ 4.3% vs. 12.8 ⁇ 4.4% freezing; P ⁇ 0.0001).
  • immediate-early gene products e.g. zif268 and c-Fos
  • c-Fos immediate-early gene products
  • the transition from recent to remote memory can be accompanied by a decrease in hippocampal activity and an increase in neocortical activity (in ACC and prefrontal cortex; Bontempi et al., 1999; Frankland et al., 2004; Hall et al., 2001; Maviel et al., 2004).
  • eNpHR3.1-mediated inhibition was delivered during training or remote recall, and assessed induction of the immediate early gene product c-Fos across the entire brain.
  • FIGS. 9D, 9G , and 9 H referenced by ( 900 ) are data of the “Control-None” group
  • ( 902 ) are data of the “NpHR-None” group
  • ( 904 ) are data of the “Control-Fear” group
  • ( 906 ) are data of the “NpHR-Fear” group.
  • No significant changes in ACC activity levels were observed at this time point.
  • Representative images of CA1, ACC and BLA are shown.
  • Anatomy is shown by DAPI nuclear staining, and the margins of the amygdala are marked with a dashed line.
  • White scalebar 150 ⁇ m.
  • mice Another group of mice was conditioned, and then re-exposed to the context 28 days after conditioning in the presence or absence of CA1 optogenetic inhibition; as before, the eNpHR3.1-expressing mice demonstrated impaired remote recall. 90 min later the brains were collected and stained for c-Fos ( FIG. 9E ) to capture putative memory-related brain-wide activity patterns under control of the hippocampus at this remote timepoint. Intriguingly, a small but significant increase in CA1c-Fos was observed in control, but not eNpHR3.1 mice ( FIG. 9F-G ; P ⁇ 0.005) following remote recall. Representative CA1, ACC and BLA images following remote memory are shown. White scalebar: 150 m.
  • FIG. 9H middle depicts global patterns in brain activity between conditioning (day 0) and remote recall (day 28).
  • Activity levels in CA1 significantly decreased in control (P ⁇ 0.005) mice from day 0 to day 28.
  • Activity levels in ACC significantly increased in both control (P ⁇ 0.0001) and eNpHR3.1 (P ⁇ 0.001) mice day 0 to day 28.
  • Activity levels in BLA significantly increased in control (P ⁇ 0.001) but not in eNHR3.1 mice.
  • FIG. 10A depicts eNpHR3.0 expression in the anterior cingulate cortex (ACC).
  • ACC anterior cingulate cortex
  • the finding that the hippocampus is still the default activator of contextual fear memory recall may be due to the fact that many place cells (Moser et al 2008) in CA1 remap in response to fear conditioning (Moita et al 2004), and may contribute to a faster recognition of the context. Indeed, hippocampal lesions were repeatedly shown to induce retrograde amnesia for spatial memory (Broadbent et al 2006; Martin et al 2005).
  • the ability to instantaneously affect cognition by optogenetic modulation of different brain areas may serve as a basis for future studies re-examining the role of specific neuronal populations in memory processes and enable a finer temporal, genetic and spatial dissection of the neuronal circuits that underlie them.
US13/882,705 2010-11-05 2011-11-04 Control and characterization of memory function Active 2031-11-09 US10086012B2 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US13/882,705 US10086012B2 (en) 2010-11-05 2011-11-04 Control and characterization of memory function

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US41073210P 2010-11-05 2010-11-05
US201161540926P 2011-09-29 2011-09-29
US13/882,705 US10086012B2 (en) 2010-11-05 2011-11-04 Control and characterization of memory function
PCT/US2011/059283 WO2012061681A1 (en) 2010-11-05 2011-11-04 Control and characterization of memory function

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2011/059283 A-371-Of-International WO2012061681A1 (en) 2010-11-05 2011-11-04 Control and characterization of memory function

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/112,202 Continuation US20190046554A1 (en) 2010-11-05 2018-08-24 Control and characterization of memory function

Publications (2)

Publication Number Publication Date
US20130343998A1 US20130343998A1 (en) 2013-12-26
US10086012B2 true US10086012B2 (en) 2018-10-02

Family

ID=46024836

Family Applications (2)

Application Number Title Priority Date Filing Date
US13/882,705 Active 2031-11-09 US10086012B2 (en) 2010-11-05 2011-11-04 Control and characterization of memory function
US16/112,202 Abandoned US20190046554A1 (en) 2010-11-05 2018-08-24 Control and characterization of memory function

Family Applications After (1)

Application Number Title Priority Date Filing Date
US16/112,202 Abandoned US20190046554A1 (en) 2010-11-05 2018-08-24 Control and characterization of memory function

Country Status (8)

Country Link
US (2) US10086012B2 (zh)
EP (1) EP2635295B1 (zh)
JP (1) JP6328424B6 (zh)
CN (2) CN103298480B (zh)
AU (2) AU2011323228B2 (zh)
CA (1) CA2816972C (zh)
ES (1) ES2661093T3 (zh)
WO (1) WO2012061681A1 (zh)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11294165B2 (en) 2017-03-30 2022-04-05 The Board Of Trustees Of The Leland Stanford Junior University Modular, electro-optical device for increasing the imaging field of view using time-sequential capture

Families Citing this family (40)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090093403A1 (en) 2007-03-01 2009-04-09 Feng Zhang Systems, methods and compositions for optical stimulation of target cells
US8926959B2 (en) 2005-07-22 2015-01-06 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US9238150B2 (en) 2005-07-22 2016-01-19 The Board Of Trustees Of The Leland Stanford Junior University Optical tissue interface method and apparatus for stimulating cells
EP1919497B1 (en) 2005-07-22 2020-02-12 The Board of Trustees of the Leland Stanford Junior University Light-activated cation channel and uses thereof
US10052497B2 (en) 2005-07-22 2018-08-21 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US9274099B2 (en) 2005-07-22 2016-03-01 The Board Of Trustees Of The Leland Stanford Junior University Screening test drugs to identify their effects on cell membrane voltage-gated ion channel
WO2008086470A1 (en) 2007-01-10 2008-07-17 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
WO2008101128A1 (en) 2007-02-14 2008-08-21 The Board Of Trustees Of The Leland Stanford Junior University System, method and applications involving identification of biological circuits such as neurological characteristics
US10035027B2 (en) 2007-10-31 2018-07-31 The Board Of Trustees Of The Leland Stanford Junior University Device and method for ultrasonic neuromodulation via stereotactic frame based technique
US10434327B2 (en) 2007-10-31 2019-10-08 The Board Of Trustees Of The Leland Stanford Junior University Implantable optical stimulators
ES2608498T3 (es) 2008-04-23 2017-04-11 The Board Of Trustees Of The Leland Stanford Junior University Sistemas, métodos y composiciones para la estimulación óptica de células diana
ES2532235T3 (es) 2008-05-29 2015-03-25 The Board Of Trustees Of The Leland Stanford Junior University Línea celular, sistema y procedimiento para el control óptico de mensajeros secundarios
CA2728238C (en) 2008-06-17 2019-03-12 M. Bret Schneider Methods, systems and devices for optical stimulation of target cells using an optical transmission element
MY162929A (en) 2008-06-17 2017-07-31 Univ Leland Stanford Junior Apparatus and methods for controlling cellular development
WO2010006049A1 (en) 2008-07-08 2010-01-14 The Board Of Trustees Of The Leland Stanford Junior University Materials and approaches for optical stimulation of the peripheral nervous system
NZ602416A (en) 2008-11-14 2014-08-29 Univ Leland Stanford Junior Optically-based stimulation of target cells and modifications thereto
EP3399024A1 (en) 2010-03-17 2018-11-07 The Board of Trustees of The Leland Stanford Junior University Light-sensitive ion-passing molecules
CA2816968C (en) 2010-11-05 2019-11-26 The Board Of Trustees Of The Leland Stanford Junior University Optically-controlled cns dysfunction
AU2011323231B2 (en) 2010-11-05 2016-01-07 The Board Of Trustees Of The Leland Stanford Junior University Upconversion of light for use in optogenetic methods
CA2816976C (en) 2010-11-05 2019-12-03 The Board Of Trustees Of The Leland Standford Junior University Optogenetic control of reward-related behaviors
WO2012061676A1 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Light-activated chimeric opsins and methods of using the same
CN103298480B (zh) * 2010-11-05 2016-10-12 斯坦福大学托管董事会 记忆功能的控制和表征
EP2635111B1 (en) * 2010-11-05 2018-05-23 The Board of Trustees of the Leland Stanford Junior University Stabilized step function opsin proteins and methods of using the same
US8696722B2 (en) 2010-11-22 2014-04-15 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic magnetic resonance imaging
CA2859364C (en) 2011-12-16 2019-05-07 The Board Of Trustees Of The Leland Stanford Junior University Opsin polypeptides and methods of use thereof
ES2728077T3 (es) 2012-02-21 2019-10-22 Univ Leland Stanford Junior Composiciones para el tratamiento de trastornos neurogénicos del suelo pélvico
US10974064B2 (en) 2013-03-15 2021-04-13 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic control of behavioral state
US9636380B2 (en) 2013-03-15 2017-05-02 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic control of inputs to the ventral tegmental area
CA2908864A1 (en) 2013-04-29 2014-11-06 The Board Of Trustees Of The Leland Stanford Junior University Devices, systems and methods for optogenetic modulation of action potentials in target cells
EP3033427A4 (en) 2013-08-14 2017-05-31 The Board Of Trustees Of The University Of the Leland Stanford Junior University Compositions and methods for controlling pain
US10052383B2 (en) 2014-03-28 2018-08-21 The Board Of Trustees Of The Leland Stanford Junior University Engineered light-activated anion channel proteins and methods of use thereof
WO2016205518A1 (en) * 2015-06-16 2016-12-22 Howard Hughes Medical Institute Methods and compositions for treating mental disorders and conditions
SG11201710519PA (en) * 2015-06-18 2018-01-30 Inter-University Res Institute Corporation National Institutes Of Natural Sciences Evaluation of inhibitory circuit and use thereof
WO2016209654A1 (en) 2015-06-22 2016-12-29 The Board Of Trustees Of The Leland Stanford Junior University Methods and devices for imaging and/or optogenetic control of light-responsive neurons
CN115569282A (zh) * 2015-11-24 2023-01-06 麻省理工学院 用于预防、减轻和/或治疗痴呆的系统和方法
CN106226509B (zh) * 2016-08-12 2019-09-06 中国人民解放军第四军医大学 一种在小鼠前扣带回皮层诱发dse现象的方法
KR20220146710A (ko) 2017-10-10 2022-11-01 메사추세츠 인스티튜트 오브 테크놀로지 치매를 예방, 경감 및/또는 치료하기 위한 시스템 및 방법
US11622948B2 (en) 2017-11-09 2023-04-11 The Trustees Of Columbia University In The City Of New York Biomarkers for efficacy of prophylactic treatments against stress-induced affective disorders
WO2022034168A1 (en) 2020-08-12 2022-02-17 Borealis Ag Multilayer film with low seal initiation temperature
CN114588263A (zh) * 2022-03-28 2022-06-07 中国人民解放军军事科学院军事医学研究院 光敏通道蛋白在空间学习记忆障碍的哺乳动物中的用途

Citations (287)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2968302A (en) 1956-07-20 1961-01-17 Univ Illinois Multibeam focusing irradiator
US3131690A (en) 1962-10-22 1964-05-05 American Optical Corp Fiber optics devices
US3499437A (en) 1967-03-10 1970-03-10 Ultrasonic Systems Method and apparatus for treatment of organic structures and systems thereof with ultrasonic energy
US3567847A (en) 1969-01-06 1971-03-02 Edgar E Price Electro-optical display system
US4343301A (en) 1979-10-04 1982-08-10 Robert Indech Subcutaneous neural stimulation or local tissue destruction
US4559951A (en) 1982-11-29 1985-12-24 Cardiac Pacemakers, Inc. Catheter assembly
US4616231A (en) 1984-03-26 1986-10-07 Hughes Aircraft Company Narrow-band beam steering system
US4865042A (en) 1985-08-16 1989-09-12 Hitachi, Ltd. Ultrasonic irradiation system
US4879284A (en) 1985-04-15 1989-11-07 L'oreal Naphthalene derivatives having retinoid type action, the process for preparation thereof and medicinal and cosmetic compositions containing them
US5032123A (en) 1989-12-28 1991-07-16 Cordis Corporation Laser catheter with radially divergent treatment beam
US5041224A (en) 1988-03-28 1991-08-20 Canon Kabushiki Kaisha Ion permeable membrane and ion transport method by utilizing said membrane
US5082670A (en) 1988-12-15 1992-01-21 The Regents Of The University Of California Method of grafting genetically modified cells to treat defects, disease or damage or the central nervous system
US5249575A (en) 1991-10-21 1993-10-05 Adm Tronics Unlimited, Inc. Corona discharge beam thermotherapy system
US5267152A (en) 1989-10-28 1993-11-30 Yang Won S Non-invasive method and apparatus for measuring blood glucose concentration
CN1079464A (zh) 1991-12-18 1993-12-15 阿斯特拉公司 治疗包括胆碱能功能降低的病症有价值的吲哚酮和吲哚二酮的衍生物的制备方法
US5290280A (en) 1989-09-08 1994-03-01 S.L.T. Japan Co., Ltd. Laser light irradiation apparatus
US5330515A (en) 1992-06-17 1994-07-19 Cyberonics, Inc. Treatment of pain by vagal afferent stimulation
US5382516A (en) 1992-09-15 1995-01-17 Schleicher & Schuell, Inc. Method and devices for delivery of substrate for the detection of enzyme-linked, membrane-based binding assays
WO1995005214A1 (en) 1993-08-16 1995-02-23 Chen James C Method and apparatus for providing light-activated therapy
US5411540A (en) 1993-06-03 1995-05-02 Massachusetts Institute Of Technology Method and apparatus for preferential neuron stimulation
US5460954A (en) 1992-04-01 1995-10-24 Cheil Foods & Chemicals, Inc. Production of human proinsulin using a novel vector system
US5460950A (en) 1990-11-26 1995-10-24 Genetics Institute, Inc. Expression of PACE in host cells and methods of use thereof
US5470307A (en) 1994-03-16 1995-11-28 Lindall; Arnold W. Catheter system for controllably releasing a therapeutic agent at a remote tissue site
US5495541A (en) 1994-04-19 1996-02-27 Murray; Steven C. Optical delivery device with high numerical aperture curved waveguide
US5520188A (en) 1994-11-02 1996-05-28 Focus Surgery Inc. Annular array transducer
US5527695A (en) 1993-01-29 1996-06-18 Purdue Research Foundation Controlled modification of eukaryotic genomes
US5550316A (en) 1991-01-02 1996-08-27 Fox Chase Cancer Center Transgenic animal model system for human cutaneous melanoma
WO1996032076A1 (en) 1995-04-11 1996-10-17 Baxter Internatonal Inc. Tissue implant systems
JPH09505771A (ja) 1994-07-25 1997-06-10 インガーソル ランド カンパニー ディスクフィルタ用空気流入絞り弁
US5641650A (en) 1993-03-25 1997-06-24 The Regents Of The University Of California Expression of heterologous polypeptides in halobacteria
US5703985A (en) 1996-04-29 1997-12-30 Eclipse Surgical Technologies, Inc. Optical fiber device and method for laser surgery procedures
US5722426A (en) 1996-02-26 1998-03-03 Kolff; Jack Coronary light probe and method of use
US5739273A (en) 1992-02-12 1998-04-14 Yale University Transmembrane polypeptide and methods of use
US5738625A (en) 1993-06-11 1998-04-14 Gluck; Daniel S. Method of and apparatus for magnetically stimulating neural cells
US5741316A (en) 1996-12-02 1998-04-21 Light Sciences Limited Partnership Electromagnetic coil configurations for power transmission through tissue
US5755750A (en) 1995-11-13 1998-05-26 University Of Florida Method and apparatus for selectively inhibiting activity in nerve fibers
US5756351A (en) 1997-01-13 1998-05-26 The Regents Of The University Of California Biomolecular optical sensors
US5782896A (en) 1997-01-29 1998-07-21 Light Sciences Limited Partnership Use of a shape memory alloy to modify the disposition of a device within an implantable medical probe
US5795581A (en) 1995-03-31 1998-08-18 Sandia Corporation Controlled release of molecular components of dendrimer/bioactive complexes
US5807285A (en) 1994-08-18 1998-09-15 Ethicon-Endo Surgery, Inc. Medical applications of ultrasonic energy
US5816256A (en) 1997-04-17 1998-10-06 Bioanalytical Systems, Inc. Movement--responsive system for conducting tests on freely-moving animals
US5836941A (en) 1993-09-07 1998-11-17 Olympus Optical Co., Ltd. Laser probe
US5898058A (en) 1996-05-20 1999-04-27 Wellman, Inc. Method of post-polymerization stabilization of high activity catalysts in continuous polyethylene terephthalate production
US5939320A (en) 1996-05-20 1999-08-17 New York University G-coupled receptors associated with macrophage-trophic HIV, and diagnostic and therapeutic uses thereof
US6056738A (en) 1997-01-31 2000-05-02 Transmedica International, Inc. Interstitial fluid monitoring
US6057114A (en) 1991-12-20 2000-05-02 Sibia Neurosciences, Inc. Automated assays and methods for detecting and modulating cell surface protein function
WO2000027293A1 (en) 1998-11-06 2000-05-18 University Of Rochester A method to improve circulation to ischemic tissue
US6108081A (en) 1998-07-20 2000-08-22 Battelle Memorial Institute Nonlinear vibrational microscopy
US6134474A (en) 1997-10-27 2000-10-17 Neuropace, Inc. Responsive implantable system for the treatment of neurological disorders
US6161045A (en) 1999-06-01 2000-12-12 Neuropace, Inc. Method for determining stimulation parameters for the treatment of epileptic seizures
US6180613B1 (en) 1994-04-13 2001-01-30 The Rockefeller University AAV-mediated delivery of DNA to cells of the nervous system
WO2001025466A1 (en) 1999-10-05 2001-04-12 Oxford Biomedica (Uk) Limited Producer cell for the production of retroviral vectors
US6253109B1 (en) 1998-11-05 2001-06-26 Medtronic Inc. System for optimized brain stimulation
US20010023346A1 (en) 1999-05-04 2001-09-20 Cardiodyne, Inc. Method and devices for creating a trap for confining therapeutic drugs and/or genes in the myocardium
US6303362B1 (en) 1998-11-19 2001-10-16 The Board Of Trustees Of The Leland Stanford Junior University Adenoviral vector and methods for making and using the same
US6334846B1 (en) 1995-03-31 2002-01-01 Kabushiki Kaisha Toshiba Ultrasound therapeutic apparatus
US6336904B1 (en) 1998-04-07 2002-01-08 Pro Duct Health, Inc. Methods and devices for the localization of lesions in solid tissue
US6346101B1 (en) 1993-07-19 2002-02-12 Research Foundation Of City College Of New York Photon-mediated introduction of biological materials into cells and/or cellular components
US6364831B1 (en) 1997-09-29 2002-04-02 Boston Scientific Corporation Endofluorescence imaging module for an endoscope
EP1197144A1 (en) 1999-07-23 2002-04-17 Xavier Estivill Palleja Transgenic mice and overexpression model of the gene ntrk3 (trkc) based thereon for the study and monitoring of treatments of anxiety, depression and related psychiatric diseases
US6377842B1 (en) 1998-09-22 2002-04-23 Aurora Optics, Inc. Method for quantitative measurement of fluorescent and phosphorescent drugs within tissue utilizing a fiber optic probe
US20020094516A1 (en) 2000-02-18 2002-07-18 Calos Michele P. Altered recombinases for genome modification
US6436708B1 (en) 1997-04-17 2002-08-20 Paola Leone Delivery system for gene therapy to the brain
US20020155173A1 (en) 1999-06-14 2002-10-24 Michael Chopp Nitric oxide donors for inducing neurogenesis
US6473639B1 (en) 2000-03-02 2002-10-29 Neuropace, Inc. Neurological event detection procedure using processed display channel based algorithms and devices incorporating these procedures
US20020164577A1 (en) 1995-06-07 2002-11-07 The Regents Of The University Of California Detection of transmembrane potentials by optical methods
US6480743B1 (en) 2000-04-05 2002-11-12 Neuropace, Inc. System and method for adaptive brain stimulation
US6489115B2 (en) 2000-12-21 2002-12-03 The Board Of Regents Of The University Of Nebraska Genetic assays for trinucleotide repeat mutations in eukaryotic cells
US20020193327A1 (en) 2000-05-01 2002-12-19 The Scripps Research Institute Vectors for occular transduction and use therefor for genetic therapy
US20020190922A1 (en) 2001-06-16 2002-12-19 Che-Chih Tsao Pattern projection techniques for volumetric 3D displays and 2D displays
US6497872B1 (en) 1991-07-08 2002-12-24 Neurospheres Holdings Ltd. Neural transplantation using proliferated multipotent neural stem cells and their progeny
US20030009103A1 (en) 1999-06-18 2003-01-09 Rafael Yuste Optical probing of neuronal connections with fluorescent indicators
US6506154B1 (en) 2000-11-28 2003-01-14 Insightec-Txsonics, Ltd. Systems and methods for controlling a phased array focused ultrasound system
US20030026784A1 (en) 1994-04-15 2003-02-06 Duke University Use of exogenous beta-adrenergic receptor and beta-adrenergic receptor kinase gene constructs to enhance myocardial function
US20030040080A1 (en) 2001-08-16 2003-02-27 Gero Miesenbock Bio-synthetic photostimulators and methods of use
US20030050258A1 (en) 1998-08-19 2003-03-13 Michele P. Calos Methods and compositions for genomic modification
US6536440B1 (en) 2000-10-17 2003-03-25 Sony Corporation Method and system for generating sensory data onto the human neural cortex
US6551346B2 (en) 2000-05-17 2003-04-22 Kent Crossley Method and apparatus to prevent infections
US20030082809A1 (en) 2001-08-23 2003-05-01 Quail Peter H. Universal light-switchable gene promoter system
US20030088060A1 (en) 2000-07-05 2003-05-08 Benjamin Christopher W Human ion channels
WO2003040323A2 (en) 2001-11-08 2003-05-15 Children's Medical Center Corporation Bacterial ion channel and a method for screening ion channel modulators
US6567690B2 (en) 2000-10-16 2003-05-20 Cole Giller Method and apparatus for probe localization in brain matter
US20030097122A1 (en) 2001-04-10 2003-05-22 Ganz Robert A. Apparatus and method for treating atherosclerotic vascular disease through light sterilization
US20030103949A1 (en) 2000-05-17 2003-06-05 Carpenter Melissa K. Screening small molecule drugs using neural cells differentiated from human embryonic stem cells
WO2003046141A2 (en) 2001-11-26 2003-06-05 Advanced Cell Technology, Inc. Methods for making and using reprogrammed human somatic cell nuclei and autologous and isogenic human stem cells
US20030104512A1 (en) 2001-11-30 2003-06-05 Freeman Alex R. Biosensors for single cell and multi cell analysis
US20030125719A1 (en) 2001-12-31 2003-07-03 Furnish Simon M. Multi-fiber catheter probe arrangement for tissue analysis or treatment
US6597954B1 (en) 1997-10-27 2003-07-22 Neuropace, Inc. System and method for controlling epileptic seizures with spatially separated detection and stimulation electrodes
US20030144650A1 (en) 2002-01-29 2003-07-31 Smith Robert F. Integrated wavefront-directed topography-controlled photoablation
US6609020B2 (en) 1999-12-01 2003-08-19 Steven Gill Neurosurgical guide device
US6615080B1 (en) 2001-03-29 2003-09-02 John Duncan Unsworth Neuromuscular electrical stimulation of the foot muscles for prevention of deep vein thrombosis and pulmonary embolism
US6631283B2 (en) 2000-11-15 2003-10-07 Virginia Tech Intellectual Properties, Inc. B/B-like fragment targeting for the purposes of photodynamic therapy and medical imaging
WO2003084994A2 (de) 2002-04-11 2003-10-16 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Verwendung von biologischen photorezeptoren als direkt lichtgesteuerte ionenkanäle
US20030204135A1 (en) 2002-04-30 2003-10-30 Alexander Bystritsky Methods for stimulating neurons
US6647296B2 (en) 1997-10-27 2003-11-11 Neuropace, Inc. Implantable apparatus for treating neurological disorders
WO2003102156A2 (en) 2002-05-31 2003-12-11 Sloan-Kettering Institute For Cancer Research Heterologous stimulus-gated ion channels and methods of using same
US20030232339A1 (en) 2002-04-01 2003-12-18 Youmin Shu Human TRPCC cation channel and uses
WO2003106486A1 (de) 2002-06-12 2003-12-24 Fraunhofer-Gelellschaft Zur Förderung Der Angewandten Forschung E.V. Pflanzliche proteinpräparate und deren verwendung
US20040013645A1 (en) 2000-06-01 2004-01-22 Monahan Paul E. Methods and compounds for controlled release of recombinant parvovirus vectors
US20040015211A1 (en) 2002-06-04 2004-01-22 Nurmikko Arto V. Optically-connected implants and related systems and methods of use
US6685656B1 (en) 1997-02-14 2004-02-03 Exogen, Inc. Ultrasonic treatment for wounds
US6686193B2 (en) 2000-07-10 2004-02-03 Vertex Pharmaceuticals, Inc. High throughput method and system for screening candidate compounds for activity against target ion channels
US20040034882A1 (en) 1999-07-15 2004-02-19 Vale Wylie W. Corticotropin releasing factor receptor 2 deficient mice and uses thereof
US20040039312A1 (en) 2002-02-20 2004-02-26 Liposonix, Inc. Ultrasonic treatment and imaging of adipose tissue
US20040049134A1 (en) 2002-07-02 2004-03-11 Tosaya Carol A. System and methods for treatment of alzheimer's and other deposition-related disorders of the brain
US20040068202A1 (en) 2000-11-30 2004-04-08 Hans-Axel Hansson System and method for automatic taking of specimens
US6721603B2 (en) 2002-01-25 2004-04-13 Cyberonics, Inc. Nerve stimulation as a treatment for pain
US20040073278A1 (en) 2001-09-04 2004-04-15 Freddy Pachys Method of and device for therapeutic illumination of internal organs and tissues
WO2004033647A2 (en) 2002-10-10 2004-04-22 Merck & Co., Inc. Assay methods for state-dependent calcium channel agonists/antagonists
US20040076613A1 (en) 2000-11-03 2004-04-22 Nicholas Mazarakis Vector system
US20040122475A1 (en) 2002-12-18 2004-06-24 Myrick Andrew J. Electrochemical neuron systems
EP1444889A1 (en) 2001-11-14 2004-08-11 Yamanouchi Pharmaceutical Co. Ltd. Transgenic animal
US6780490B1 (en) 1999-08-06 2004-08-24 Yukadenshi Co., Ltd. Tray for conveying magnetic head for magnetic disk
US6790657B1 (en) 1999-01-07 2004-09-14 The United States Of America As Represented By The Department Of Health And Human Services Lentivirus vector system
US6790652B1 (en) 1998-01-08 2004-09-14 Bioimage A/S Method and apparatus for high density format screening for bioactive molecules
US6805129B1 (en) 1996-10-22 2004-10-19 Epicor Medical, Inc. Apparatus and method for ablating tissue
US6810285B2 (en) 2001-06-28 2004-10-26 Neuropace, Inc. Seizure sensing and detection using an implantable device
US6808873B2 (en) 2000-01-14 2004-10-26 Mitokor, Inc. Screening assays using intramitochondrial calcium
US20040216177A1 (en) 2003-04-25 2004-10-28 Otsuka Pharmaceutical Co., Ltd. Congenic rats containing a mutant GPR10 gene
JP2004534508A (ja) 2000-11-16 2004-11-18 リサーチ　ディベロップメント　ファンデーション コルチコトロピン放出因子レセプタ２欠失マウスとその利用
CN1558222A (zh) 2004-02-03 2004-12-29 复旦大学 生物光敏蛋白-纳米半导体复合光电极的制备方法
US20040267118A1 (en) 2000-10-17 2004-12-30 Sony Corporation/Sony Electronics Inc. Scanning method for applying ultrasonic acoustic data to the human neural cortex
US20050020945A1 (en) 2002-07-02 2005-01-27 Tosaya Carol A. Acoustically-aided cerebrospinal-fluid manipulation for neurodegenerative disease therapy
US20050027284A1 (en) 2003-06-19 2005-02-03 Advanced Neuromodulation Systems, Inc. Method of treating depression, mood disorders and anxiety disorders using neuromodulation
JP2005034073A (ja) 2003-07-16 2005-02-10 Masamitsu Iino ミオシン軽鎖リン酸化の測定用蛍光性プローブ
US20050058987A1 (en) 2002-11-18 2005-03-17 Pei-Yong Shi Screening for west nile virus antiviral therapy
US20050088177A1 (en) 2003-10-22 2005-04-28 Oliver Schreck Method for slice position planning of tomographic measurements, using statistical images
US6889085B2 (en) 2000-10-17 2005-05-03 Sony Corporation Method and system for forming an acoustic signal from neural timing difference data
US20050107753A1 (en) 2002-02-01 2005-05-19 Ali Rezai Microinfusion device
US20050112759A1 (en) 2003-06-20 2005-05-26 Milica Radisic Application of electrical stimulation for functional tissue engineering in vitro and in vivo
US20050119315A1 (en) 1999-03-31 2005-06-02 Cardiome Pharma Corp. Ion channel modulating activity II
US20050124897A1 (en) 2003-12-03 2005-06-09 Scimed Life Systems, Inc. Apparatus and methods for delivering acoustic energy to body tissue
US20050143790A1 (en) 2003-10-21 2005-06-30 Kipke Daryl R. Intracranial neural interface system
US20050143295A1 (en) 2001-04-04 2005-06-30 Irm Llc Methods for treating drug addiction
US20050153885A1 (en) 2003-10-08 2005-07-14 Yun Anthony J. Treatment of conditions through modulation of the autonomic nervous system
US6918872B2 (en) 2002-03-08 2005-07-19 Olympus Corporation Capsule endoscope
US6921413B2 (en) 2000-08-16 2005-07-26 Vanderbilt University Methods and devices for optical stimulation of neural tissues
US20050215764A1 (en) 2004-03-24 2005-09-29 Tuszynski Jack A Biological polymer with differently charged portions
WO2005093429A2 (en) 2004-03-26 2005-10-06 Brini, Marisa Method for the detection of intracellular parameters with luminescent protein probes for the screening of molecules capable of altering said parameters
US20050240127A1 (en) 2004-03-02 2005-10-27 Ralf Seip Ultrasound phased arrays
US20050267454A1 (en) 2000-01-19 2005-12-01 Medtronic, Inc. Methods of using high intensity focused ultrasound to form an ablated tissue area containing a plurality of lesions
US20050267011A1 (en) 2004-05-24 2005-12-01 The Board Of Trustees Of The Leland Stanford Junior University Coupling of excitation and neurogenesis in neural stem/progenitor cells
US6974448B2 (en) 2001-08-30 2005-12-13 Medtronic, Inc. Method for convection enhanced delivery catheter to treat brain and other tumors
US20050279354A1 (en) 2004-06-21 2005-12-22 Harvey Deutsch Structures and Methods for the Joint Delivery of Fluids and Light
US20060025756A1 (en) 2000-01-19 2006-02-02 Francischelli David E Methods of using high intensity focused ultrasound to form an ablated tissue area
US20060034943A1 (en) 2003-10-31 2006-02-16 Technology Innovations Llc Process for treating a biological organism
US20060058671A1 (en) 2004-08-11 2006-03-16 Insightec-Image Guided Treatment Ltd Focused ultrasound system with adaptive anatomical aperture shaping
US20060057192A1 (en) 2001-09-28 2006-03-16 Kane Patrick D Localized non-invasive biological modulation system
US20060058678A1 (en) 2004-08-26 2006-03-16 Insightec - Image Guided Treatment Ltd. Focused ultrasound system for surrounding a body tissue mass
US20060057614A1 (en) 2004-08-04 2006-03-16 Nathaniel Heintz Tethering neuropeptides and toxins for modulation of ion channels and receptors
US20060100679A1 (en) 2004-08-27 2006-05-11 Dimauro Thomas Light-based implants for treating Alzheimer's disease
US20060106543A1 (en) 2002-08-09 2006-05-18 Gustavo Deco Method for analyzing effectiveness of pharmaceutical preparation
US20060155348A1 (en) 2004-11-15 2006-07-13 Decharms Richard C Applications of the stimulation of neural tissue using light
US20060161227A1 (en) 2004-11-12 2006-07-20 Northwestern University Apparatus and methods for optical stimulation of the auditory nerve
US20060167500A1 (en) 2002-08-19 2006-07-27 Bruce Towe Neurostimulator
US20060179501A1 (en) 2002-12-16 2006-08-10 Chan Andrew C Transgenic mice expressing human cd20
US7091500B2 (en) 2003-06-20 2006-08-15 Lucent Technologies Inc. Multi-photon endoscopic imaging system
US20060184069A1 (en) 2005-02-02 2006-08-17 Vaitekunas Jeffrey J Focused ultrasound for pain reduction
JP2006217866A (ja) 2005-02-10 2006-08-24 Tohoku Univ 光感受性を新たに賦与した神経細胞
US20060190044A1 (en) 2005-02-22 2006-08-24 Cardiac Pacemakers, Inc. Cell therapy and neural stimulation for cardiac repair
US20060206172A1 (en) 2005-03-14 2006-09-14 Dimauro Thomas M Red light implant for treating Parkinson's Disease
WO2006103678A2 (en) 2005-03-31 2006-10-05 Esther Mayer Probe device, system and method for photobiomodulation of tissue lining a body cavity
US20060236525A1 (en) 2005-04-11 2006-10-26 Jack Sliwa High intensity ultrasound transducers and methods and devices for manufacturing high intensity ultrasound transducers
JP2006295350A (ja) 2005-04-07 2006-10-26 Sony Corp 撮像装置及び撮像結果の処理方法
US20060241697A1 (en) 2005-04-25 2006-10-26 Cardiac Pacemakers, Inc. System to provide neural markers for sensed neural activity
US20060253177A1 (en) 2001-11-01 2006-11-09 Taboada Luis D Device and method for providing phototherapy to the brain
US20060271024A1 (en) 2005-01-25 2006-11-30 Michael Gertner Nasal Cavity Treatment Apparatus
US20070027443A1 (en) 2005-06-29 2007-02-01 Ondine International, Ltd. Hand piece for the delivery of light and system employing the hand piece
US20070031924A1 (en) 2003-11-21 2007-02-08 The Johns Hopkins University Biomolecule partition motifs and uses thereof
US7175596B2 (en) 2001-10-29 2007-02-13 Insightec-Txsonics Ltd System and method for sensing and locating disturbances in an energy path of a focused ultrasound system
WO2007024391A2 (en) 2005-07-22 2007-03-01 The Board Of Trustees Of The Leland Stanford Junior University Light-activated cation channel and uses thereof
US7191018B2 (en) 1998-04-30 2007-03-13 Medtronic, Inc. Techniques for positioning therapy delivery elements within a spinal cord or brain
US20070060984A1 (en) 2005-09-09 2007-03-15 Webb James S Apparatus and method for optical stimulation of nerves and other animal tissue
US20070060915A1 (en) 2005-09-15 2007-03-15 Cannuflow, Inc. Arthroscopic surgical temperature control system
US7220240B2 (en) 2000-05-03 2007-05-22 Aspect Medical Systems, Inc. System and method for adaptive drug delivery
US20070135875A1 (en) 2002-04-08 2007-06-14 Ardian, Inc. Methods and apparatus for thermally-induced renal neuromodulation
US20070156180A1 (en) 2005-12-30 2007-07-05 Jaax Kristen N Methods and systems for treating osteoarthritis
US20070191906A1 (en) 2006-02-13 2007-08-16 Anand Iyer Method and apparatus for selective nerve stimulation
US20070196838A1 (en) 2000-12-08 2007-08-23 Invitrogen Corporation Methods and compositions for synthesis of nucleic acid molecules using multiple recognition sites
US20070197918A1 (en) 2003-06-02 2007-08-23 Insightec - Image Guided Treatment Ltd. Endo-cavity focused ultrasound transducer
US20070220628A1 (en) 2005-12-21 2007-09-20 Pioneer Hi-Bred International, Inc. Methods and compositions for in planta production of inverted repeats
US20070219600A1 (en) 2006-03-17 2007-09-20 Michael Gertner Devices and methods for targeted nasal phototherapy
US20070239210A1 (en) 2006-04-10 2007-10-11 Imad Libbus System and method for closed-loop neural stimulation
US20070239080A1 (en) 2004-10-22 2007-10-11 Wolfgang Schaden Methods for promoting nerve regeneration and neuronal growth and elongation
US20070253995A1 (en) 2006-04-28 2007-11-01 Medtronic, Inc. Drug Delivery Methods and Devices for Treating Stress Urinary Incontinence
US20070260295A1 (en) 2006-05-03 2007-11-08 Light Sciences Corporation Light transmission system for photoreactive therapy
WO2007131180A2 (en) 2006-05-04 2007-11-15 Wayne State University Restoration of visual responses by in vivo delivery of rhodopsin nucleic acids
US7298143B2 (en) 2002-05-13 2007-11-20 Koninklijke Philips Electronics N.V. Reduction of susceptibility artifacts in subencoded single-shot magnetic resonance imaging
US20070282404A1 (en) 2006-04-10 2007-12-06 University Of Rochester Side-firing linear optic array for interstitial optical therapy and monitoring using compact helical geometry
US7313442B2 (en) 2004-04-30 2007-12-25 Advanced Neuromodulation Systems, Inc. Method of treating mood disorders and/or anxiety disorders by brain stimulation
US20070295978A1 (en) 2006-06-26 2007-12-27 Coushaine Charles M Light emitting diode with direct view optic
US20080020465A1 (en) 2005-02-02 2008-01-24 Malla Padidam Site-specific serine recombinases and methods of their use
WO2008014382A2 (en) 2006-07-26 2008-01-31 Case Western Reserve University System and method for controlling g-protein coupled receptor pathways
US20080027505A1 (en) 2006-07-26 2008-01-31 G&L Consulting, Llc System and method for treatment of headaches
US20080033569A1 (en) 2004-04-19 2008-02-07 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Bioelectromagnetic interface system
US20080046053A1 (en) 2006-06-19 2008-02-21 Wagner Timothy A Apparatus and method for stimulation of biological tissue
US20080051673A1 (en) 2006-08-17 2008-02-28 Xuan Kong Motor unit number estimation (MUNE) for the assessment of neuromuscular function
US20080050770A1 (en) 1998-12-01 2008-02-28 Introgen Therapeutics, Inc. Method for the production and purification of adenoviral vectors
US20080060088A1 (en) 2006-09-01 2008-03-06 Heesup Shin Phospholipase c beta1 (plcbeta1) knockout mice as a model system for testing schizophrenia drugs
US20080065183A1 (en) 2002-06-20 2008-03-13 Advanced Bionics Corporation Vagus nerve stimulation via unidirectional propagation of action potentials
US20080065158A1 (en) 2006-09-07 2008-03-13 Omry Ben-Ezra Techniques for reducing pain associated with nerve stimulation
US20080077200A1 (en) 2006-09-21 2008-03-27 Aculight Corporation Apparatus and method for stimulation of nerves and automated control of surgical instruments
US20080085265A1 (en) 2005-07-22 2008-04-10 Schneider M B System for optical stimulation of target cells
US20080088258A1 (en) 2006-07-28 2008-04-17 Stmicroelectronics Asia Pacific Pte Ltd Addressable LED architecture
US20080103551A1 (en) 2006-10-30 2008-05-01 Javaid Masoud Implantable Medical Device with Variable Data Retransmission Characteristics Based Upon Data Type
US20080119421A1 (en) 2003-10-31 2008-05-22 Jack Tuszynski Process for treating a biological organism
US20080125836A1 (en) 2006-08-24 2008-05-29 Jackson Streeter Low level light therapy for enhancement of neurologic function of a patient affected by parkinson's disease
WO2008086470A1 (en) 2007-01-10 2008-07-17 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US20080175819A1 (en) 1997-06-04 2008-07-24 Oxford Biomedica (Uk) Limited Vector system
US20080176076A1 (en) 2006-05-11 2008-07-24 University Of Victoria Innovation And Development Corporation Functionalized lanthanide rich nanoparticles and use thereof
US20080200749A1 (en) 2005-06-15 2008-08-21 Yunfeng Zheng Magnetic Stimulating Circuit For Nervous Centralis System Apparatus, Purpose, and Method Thereof
WO2008106694A2 (en) 2007-03-01 2008-09-04 The Board Of Trustees Of The Leland Stanford Junior University Systems, methods and compositions for optical stimulation of target cells
US20080221452A1 (en) 2007-03-09 2008-09-11 Philip Chidi Njemanze Method for inducing and monitoring long-term potentiation and long-term depression using transcranial doppler ultrasound device in head-down bed rest
US20080227139A1 (en) 2007-02-14 2008-09-18 Karl Deisseroth System, method and applications involving identification of biological circuits such as neurological characteristics
US20080228244A1 (en) 2007-03-16 2008-09-18 Old Dominion University Modulation of neuromuscular functions with ultrashort electrical pulses
US20080262411A1 (en) 2006-06-02 2008-10-23 Dobak John D Dynamic nerve stimulation in combination with other eating disorder treatment modalities
US20080287821A1 (en) 2007-03-30 2008-11-20 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational user-health testing
US20080290318A1 (en) 2005-04-26 2008-11-27 Van Veggel Franciscus C J M Production of Light from Sol-Gel Derived Thin Films Made with Lanthanide Doped Nanoparticles, and Preparation Thereof
US20090030930A1 (en) 2007-05-01 2009-01-29 Neurofocus Inc. Neuro-informatics repository system
WO2009025819A1 (en) 2007-08-22 2009-02-26 Cardiac Pacemakers, Inc. Optical depolarization of cardiac tissue
US20090069261A1 (en) 2005-05-02 2009-03-12 Genzyme Corporation Gene therapy for spinal cord disorders
US20090088680A1 (en) 2005-07-22 2009-04-02 Alexander Aravanis Optical tissue interface method and apparatus for stimulating cells
US20090099038A1 (en) 2005-07-22 2009-04-16 Karl Deisseroth Cell line, system and method for optical-based screening of ion-channel modulators
US20090112133A1 (en) 2007-10-31 2009-04-30 Karl Deisseroth Device and method for non-invasive neuromodulation
US20090118800A1 (en) 2007-10-31 2009-05-07 Karl Deisseroth Implantable optical stimulators
US20090131837A1 (en) 2005-04-23 2009-05-21 Smith & Nephew, Plc Ultrasound Device
US20090148861A1 (en) 2007-06-20 2009-06-11 The Salk Institute Kir channel modulators
WO2009072123A2 (en) 2007-12-06 2009-06-11 Technion Research & Development Foundation Ltd. Method and system for optical stimulation of neurons
US20090157145A1 (en) 2007-11-26 2009-06-18 Lawrence Cauller Transfer Coil Architecture
WO2009119782A1 (ja) 2008-03-24 2009-10-01 国立大学法人東北大学 改変された光受容体チャネル型ロドプシンタンパク質
US20090254134A1 (en) 2008-02-04 2009-10-08 Medtrode Inc. Hybrid ultrasound/electrode device for neural stimulation and recording
US7603174B2 (en) 2004-10-21 2009-10-13 Advanced Neuromodulation Systems, Inc. Stimulation of the amygdalohippocampal complex to treat neurological conditions
WO2009131837A2 (en) 2008-04-23 2009-10-29 The Board Of Trustees Of The Leland Stanford Junior University. Systems, methods and compositions for optical stimulation of target cells
US20090268511A1 (en) 2008-01-16 2009-10-29 University Of Connecticut Bacteriorhodopsin Protein Variants and Methods of Use for Long Term Data Storage
WO2009148946A2 (en) 2008-05-29 2009-12-10 The Board Of Trustees Of The Leland Stanford Junior University Cell line, system and method for optical control of secondary messengers
US20090306474A1 (en) 2008-06-09 2009-12-10 Capso Vision, Inc. In vivo camera with multiple sources to illuminate tissue at different distances
US20090326603A1 (en) 2003-09-12 2009-12-31 Case Western Reserve University Apparatus for stimulating components in, on, or near the pudendal nerve or its branches to achieve selective physiologic responses
WO2010006049A1 (en) 2008-07-08 2010-01-14 The Board Of Trustees Of The Leland Stanford Junior University Materials and approaches for optical stimulation of the peripheral nervous system
US20100016783A1 (en) 2008-04-04 2010-01-21 Duke University Non-invasive systems and methods for in-situ photobiomodulation
US20100021982A1 (en) 2006-12-06 2010-01-28 Stefan Herlitze Light-sensitive constructs for inducing cell death and cell signaling
WO2010011404A2 (en) 2008-05-20 2010-01-28 Eos Neuroscience, Inc. Vectors for delivery of light-sensitive proteins and methods of use
US7686839B2 (en) 2005-01-26 2010-03-30 Lumitex, Inc. Phototherapy treatment devices for applying area lighting to a wound
WO2010056970A2 (en) 2008-11-14 2010-05-20 The Board Of Trustees Of The Leland Stanford Junior University Optically-based stimulation of target cells and modifications thereto
US20100146645A1 (en) 2006-12-12 2010-06-10 Eero Vasar Transgenic animal model for modelling pathological anxiety, a method for identifying compounds for treatment of diseases or disorders caused by pathological anxiety and a method for using wfs1 protein as a target for identifying effective compounds against pathological anxiety
US20100190229A1 (en) 2005-07-22 2010-07-29 Feng Zhang System for optical stimulation of target cells
US20100209352A1 (en) 2005-03-29 2010-08-19 The Trustees Of Columbia University In The City Of Synthesis and conjugation of iron oxide nanoparticles to antibodies for targeting specific cells using fluorescence and mr imaging techniques
JP2010227537A (ja) 2009-03-25 2010-10-14 Korea Inst Of Science & Technology 光刺激装置
WO2010123993A1 (en) 2009-04-21 2010-10-28 Tuan Vo-Dinh Non-invasive energy upconversion methods and systems for in-situ photobiomodulation
WO2011005978A2 (en) 2009-07-08 2011-01-13 Duke University Methods of manipulating cell signaling
US20110021270A1 (en) 2002-09-13 2011-01-27 Bally Gaming, Inc. Device verification system and method
US7883536B1 (en) 2007-01-19 2011-02-08 Lockheed Martin Corporation Hybrid optical-electrical probes
US20110092800A1 (en) 2002-04-30 2011-04-21 Seung-Schik Yoo Methods for modifying electrical currents in neuronal circuits
US20110112463A1 (en) 2009-11-12 2011-05-12 Jerry Silver Compositions and methods for treating a neuronal injury or neuronal disorders
US20110125077A1 (en) 2009-11-25 2011-05-26 Medtronic, Inc. Optical stimulation therapy
US20110159562A1 (en) 2008-06-17 2011-06-30 Karl Deisseroth Apparatus and methods for controlling cellular development
US20110165681A1 (en) 2009-02-26 2011-07-07 Massachusetts Institute Of Technology Light-Activated Proton Pumps and Applications Thereof
US20110172653A1 (en) 2008-06-17 2011-07-14 Schneider M Bret Methods, systems and devices for optical stimulation of target cells using an optical transmission element
WO2011106783A2 (en) 2010-02-26 2011-09-01 Cornell University Retina prosthesis
WO2011116238A2 (en) 2010-03-17 2011-09-22 The Board Of Trustees Of The Leland Stanford Junior University. Light-sensitive ion-passing molecules
US20110233046A1 (en) 2008-09-25 2011-09-29 The Trustees Of Columbia University In The City Of New York Devices, apparatus and method for providing photostimulation and imaging of structures
WO2011127088A2 (en) 2010-04-05 2011-10-13 Eos Neuroscience, Inc. Methods and compositions for decreasing chronic pain
WO2012032103A1 (en) 2010-09-08 2012-03-15 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Mutant channelrhodopsin 2
WO2012061688A1 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic control of reward-related behaviors
WO2012061681A1 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University. Control and characterization of memory function
WO2012061744A2 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Stabilized step function opsin proteins and methods of using the same
WO2012061676A1 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Light-activated chimeric opsins and methods of using the same
WO2012061690A2 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Optically-controlled cns dysfunction
WO2012061684A1 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Upconversion of light for use in optogenetic methods
WO2012061741A2 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University. Control and characterization of psychotic states
US20120121542A1 (en) 2010-11-13 2012-05-17 Amy Chuong Red-shifted opsin molecules and uses thereof
US20120165904A1 (en) 2010-11-22 2012-06-28 Jin Hyung Lee Optogenetic magnetic resonance imaging
WO2012106407A2 (en) 2011-02-01 2012-08-09 The University Of Vermont And State Agricultural College Diagnostic and therapeutic methods and products related to anxiety disorders
US20120253261A1 (en) 2011-03-29 2012-10-04 Medtronic, Inc. Systems and methods for optogenetic modulation of cells within a patient
WO2013003557A1 (en) 2011-06-28 2013-01-03 University Of Rochester Photoactivatable receptors and their uses
US20130030275A1 (en) 2011-07-25 2013-01-31 Seymour John P Opto-electrical device and method for artifact reduction
WO2013016486A1 (en) 2011-07-27 2013-01-31 The Board Of Trustees Of The University Of Illinois Nanopore sensors for biomolecular characterization
US20130144359A1 (en) 2009-03-24 2013-06-06 Eyad Kishawi Pain management with stimulation subthreshold to paresthesia
WO2013090356A2 (en) 2011-12-16 2013-06-20 The Board Of Trustees Of The Leland Stanford Junior University Opsin polypeptides and methods of use thereof
WO2013126521A1 (en) 2012-02-21 2013-08-29 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for treating neurogenic disorders of the pelvic floor
WO2013126762A1 (en) 2012-02-23 2013-08-29 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Office Of Technology Transfer, National Institutes Of Health Multi-focal structured illumination microscopy systems and methods
WO2013142196A1 (en) 2012-03-20 2013-09-26 The Board Of Trustees Of The Leland Stanford Junior University Non-human animal models of depression and methods of use thereof
US20130286181A1 (en) 2010-06-14 2013-10-31 Howard Hughes Medical Institute Structured plane illumination microscopy
WO2014081449A1 (en) 2012-11-21 2014-05-30 Circuit Therapeutics, Inc. System and method for optogenetic therapy
WO2014117079A1 (en) 2013-01-25 2014-07-31 The Trustees Of Columbia University In The City Of New York Depth of field 3d imaging slm microscope
US20150112411A1 (en) 2013-10-18 2015-04-23 Varaya Photoceuticals, Llc High powered light emitting diode photobiology compositions, methods and systems
US9057734B2 (en) 2010-08-23 2015-06-16 President And Fellows Of Harvard College Optogenetic probes for measuring membrane potential
WO2016019075A1 (en) 2014-07-29 2016-02-04 Circuit Therapeutics, Inc. System and method for optogenetic therapy

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001011034A2 (en) 1999-08-09 2001-02-15 Targeted Genetics Corporation Enhancement of expression of a single-stranded, heterologous nucleotide sequence from recombinant viral vectors by designing the sequence such that it forms intrastrand base pairs
JP2006519609A (ja) * 2003-03-12 2006-08-31 サマリタン・ファーマシューティカルズ・インコーポレイテッド 神経疾患擬態動物モデル
CN101288768A (zh) * 2007-04-20 2008-10-22 中央研究院 用于治疗渐进神经退化症的医药组合物

Patent Citations (341)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2968302A (en) 1956-07-20 1961-01-17 Univ Illinois Multibeam focusing irradiator
US3131690A (en) 1962-10-22 1964-05-05 American Optical Corp Fiber optics devices
US3499437A (en) 1967-03-10 1970-03-10 Ultrasonic Systems Method and apparatus for treatment of organic structures and systems thereof with ultrasonic energy
US3567847A (en) 1969-01-06 1971-03-02 Edgar E Price Electro-optical display system
US4343301A (en) 1979-10-04 1982-08-10 Robert Indech Subcutaneous neural stimulation or local tissue destruction
US4559951A (en) 1982-11-29 1985-12-24 Cardiac Pacemakers, Inc. Catheter assembly
US4616231A (en) 1984-03-26 1986-10-07 Hughes Aircraft Company Narrow-band beam steering system
US4879284A (en) 1985-04-15 1989-11-07 L'oreal Naphthalene derivatives having retinoid type action, the process for preparation thereof and medicinal and cosmetic compositions containing them
US4865042A (en) 1985-08-16 1989-09-12 Hitachi, Ltd. Ultrasonic irradiation system
US5041224A (en) 1988-03-28 1991-08-20 Canon Kabushiki Kaisha Ion permeable membrane and ion transport method by utilizing said membrane
US5082670A (en) 1988-12-15 1992-01-21 The Regents Of The University Of California Method of grafting genetically modified cells to treat defects, disease or damage or the central nervous system
US5290280A (en) 1989-09-08 1994-03-01 S.L.T. Japan Co., Ltd. Laser light irradiation apparatus
US5267152A (en) 1989-10-28 1993-11-30 Yang Won S Non-invasive method and apparatus for measuring blood glucose concentration
US5032123A (en) 1989-12-28 1991-07-16 Cordis Corporation Laser catheter with radially divergent treatment beam
US5460950A (en) 1990-11-26 1995-10-24 Genetics Institute, Inc. Expression of PACE in host cells and methods of use thereof
US5550316A (en) 1991-01-02 1996-08-27 Fox Chase Cancer Center Transgenic animal model system for human cutaneous melanoma
US6497872B1 (en) 1991-07-08 2002-12-24 Neurospheres Holdings Ltd. Neural transplantation using proliferated multipotent neural stem cells and their progeny
US5249575A (en) 1991-10-21 1993-10-05 Adm Tronics Unlimited, Inc. Corona discharge beam thermotherapy system
CN1079464A (zh) 1991-12-18 1993-12-15 阿斯特拉公司 治疗包括胆碱能功能降低的病症有价值的吲哚酮和吲哚二酮的衍生物的制备方法
US6057114A (en) 1991-12-20 2000-05-02 Sibia Neurosciences, Inc. Automated assays and methods for detecting and modulating cell surface protein function
US5739273A (en) 1992-02-12 1998-04-14 Yale University Transmembrane polypeptide and methods of use
US5460954A (en) 1992-04-01 1995-10-24 Cheil Foods & Chemicals, Inc. Production of human proinsulin using a novel vector system
US5330515A (en) 1992-06-17 1994-07-19 Cyberonics, Inc. Treatment of pain by vagal afferent stimulation
US5382516A (en) 1992-09-15 1995-01-17 Schleicher & Schuell, Inc. Method and devices for delivery of substrate for the detection of enzyme-linked, membrane-based binding assays
US5527695A (en) 1993-01-29 1996-06-18 Purdue Research Foundation Controlled modification of eukaryotic genomes
US5641650A (en) 1993-03-25 1997-06-24 The Regents Of The University Of California Expression of heterologous polypeptides in halobacteria
US5411540A (en) 1993-06-03 1995-05-02 Massachusetts Institute Of Technology Method and apparatus for preferential neuron stimulation
US5738625A (en) 1993-06-11 1998-04-14 Gluck; Daniel S. Method of and apparatus for magnetically stimulating neural cells
US6346101B1 (en) 1993-07-19 2002-02-12 Research Foundation Of City College Of New York Photon-mediated introduction of biological materials into cells and/or cellular components
US5445608A (en) 1993-08-16 1995-08-29 James C. Chen Method and apparatus for providing light-activated therapy
EP1334748A1 (en) 1993-08-16 2003-08-13 Light Sciences Corporation Apparatus for photodynamic therapy
WO1995005214A1 (en) 1993-08-16 1995-02-23 Chen James C Method and apparatus for providing light-activated therapy
US5836941A (en) 1993-09-07 1998-11-17 Olympus Optical Co., Ltd. Laser probe
US5470307A (en) 1994-03-16 1995-11-28 Lindall; Arnold W. Catheter system for controllably releasing a therapeutic agent at a remote tissue site
US6180613B1 (en) 1994-04-13 2001-01-30 The Rockefeller University AAV-mediated delivery of DNA to cells of the nervous system
US20030026784A1 (en) 1994-04-15 2003-02-06 Duke University Use of exogenous beta-adrenergic receptor and beta-adrenergic receptor kinase gene constructs to enhance myocardial function
US5495541A (en) 1994-04-19 1996-02-27 Murray; Steven C. Optical delivery device with high numerical aperture curved waveguide
JPH09505771A (ja) 1994-07-25 1997-06-10 インガーソル ランド カンパニー ディスクフィルタ用空気流入絞り弁
US5807285A (en) 1994-08-18 1998-09-15 Ethicon-Endo Surgery, Inc. Medical applications of ultrasonic energy
US5520188A (en) 1994-11-02 1996-05-28 Focus Surgery Inc. Annular array transducer
US5795581A (en) 1995-03-31 1998-08-18 Sandia Corporation Controlled release of molecular components of dendrimer/bioactive complexes
US6334846B1 (en) 1995-03-31 2002-01-01 Kabushiki Kaisha Toshiba Ultrasound therapeutic apparatus
WO1996032076A1 (en) 1995-04-11 1996-10-17 Baxter Internatonal Inc. Tissue implant systems
US20020164577A1 (en) 1995-06-07 2002-11-07 The Regents Of The University Of California Detection of transmembrane potentials by optical methods
US5755750A (en) 1995-11-13 1998-05-26 University Of Florida Method and apparatus for selectively inhibiting activity in nerve fibers
US5722426A (en) 1996-02-26 1998-03-03 Kolff; Jack Coronary light probe and method of use
US5703985A (en) 1996-04-29 1997-12-30 Eclipse Surgical Technologies, Inc. Optical fiber device and method for laser surgery procedures
US5898058A (en) 1996-05-20 1999-04-27 Wellman, Inc. Method of post-polymerization stabilization of high activity catalysts in continuous polyethylene terephthalate production
US5939320A (en) 1996-05-20 1999-08-17 New York University G-coupled receptors associated with macrophage-trophic HIV, and diagnostic and therapeutic uses thereof
US6805129B1 (en) 1996-10-22 2004-10-19 Epicor Medical, Inc. Apparatus and method for ablating tissue
US5741316A (en) 1996-12-02 1998-04-21 Light Sciences Limited Partnership Electromagnetic coil configurations for power transmission through tissue
US5756351A (en) 1997-01-13 1998-05-26 The Regents Of The University Of California Biomolecular optical sensors
US5782896A (en) 1997-01-29 1998-07-21 Light Sciences Limited Partnership Use of a shape memory alloy to modify the disposition of a device within an implantable medical probe
US6056738A (en) 1997-01-31 2000-05-02 Transmedica International, Inc. Interstitial fluid monitoring
US6685656B1 (en) 1997-02-14 2004-02-03 Exogen, Inc. Ultrasonic treatment for wounds
US6436708B1 (en) 1997-04-17 2002-08-20 Paola Leone Delivery system for gene therapy to the brain
US5816256A (en) 1997-04-17 1998-10-06 Bioanalytical Systems, Inc. Movement--responsive system for conducting tests on freely-moving animals
US20080175819A1 (en) 1997-06-04 2008-07-24 Oxford Biomedica (Uk) Limited Vector system
US6364831B1 (en) 1997-09-29 2002-04-02 Boston Scientific Corporation Endofluorescence imaging module for an endoscope
US6647296B2 (en) 1997-10-27 2003-11-11 Neuropace, Inc. Implantable apparatus for treating neurological disorders
US6134474A (en) 1997-10-27 2000-10-17 Neuropace, Inc. Responsive implantable system for the treatment of neurological disorders
US6597954B1 (en) 1997-10-27 2003-07-22 Neuropace, Inc. System and method for controlling epileptic seizures with spatially separated detection and stimulation electrodes
US6790652B1 (en) 1998-01-08 2004-09-14 Bioimage A/S Method and apparatus for high density format screening for bioactive molecules
US6336904B1 (en) 1998-04-07 2002-01-08 Pro Duct Health, Inc. Methods and devices for the localization of lesions in solid tissue
US7191018B2 (en) 1998-04-30 2007-03-13 Medtronic, Inc. Techniques for positioning therapy delivery elements within a spinal cord or brain
US6108081A (en) 1998-07-20 2000-08-22 Battelle Memorial Institute Nonlinear vibrational microscopy
US20040203152A1 (en) 1998-08-19 2004-10-14 Calos Michele P. Methods and compositions for genomic modification
US20030050258A1 (en) 1998-08-19 2003-03-13 Michele P. Calos Methods and compositions for genomic modification
US6632672B2 (en) 1998-08-19 2003-10-14 The Board Of Trustees Of The Leland Stanford Junior University Methods and compositions for genomic modification
US6377842B1 (en) 1998-09-22 2002-04-23 Aurora Optics, Inc. Method for quantitative measurement of fluorescent and phosphorescent drugs within tissue utilizing a fiber optic probe
US6253109B1 (en) 1998-11-05 2001-06-26 Medtronic Inc. System for optimized brain stimulation
WO2000027293A1 (en) 1998-11-06 2000-05-18 University Of Rochester A method to improve circulation to ischemic tissue
US7211054B1 (en) 1998-11-06 2007-05-01 University Of Rochester Method of treating a patient with a neurodegenerative disease using ultrasound
US6303362B1 (en) 1998-11-19 2001-10-16 The Board Of Trustees Of The Leland Stanford Junior University Adenoviral vector and methods for making and using the same
US7045344B2 (en) 1998-11-19 2006-05-16 The Board Of Trustees Of The Leland Stanford Junior University Adenoviral vector and methods for making and using the same
US20080050770A1 (en) 1998-12-01 2008-02-28 Introgen Therapeutics, Inc. Method for the production and purification of adenoviral vectors
US6790657B1 (en) 1999-01-07 2004-09-14 The United States Of America As Represented By The Department Of Health And Human Services Lentivirus vector system
US20050119315A1 (en) 1999-03-31 2005-06-02 Cardiome Pharma Corp. Ion channel modulating activity II
US20010023346A1 (en) 1999-05-04 2001-09-20 Cardiodyne, Inc. Method and devices for creating a trap for confining therapeutic drugs and/or genes in the myocardium
US6161045A (en) 1999-06-01 2000-12-12 Neuropace, Inc. Method for determining stimulation parameters for the treatment of epileptic seizures
US20020155173A1 (en) 1999-06-14 2002-10-24 Michael Chopp Nitric oxide donors for inducing neurogenesis
US20030009103A1 (en) 1999-06-18 2003-01-09 Rafael Yuste Optical probing of neuronal connections with fluorescent indicators
US20040034882A1 (en) 1999-07-15 2004-02-19 Vale Wylie W. Corticotropin releasing factor receptor 2 deficient mice and uses thereof
EP1197144A1 (en) 1999-07-23 2002-04-17 Xavier Estivill Palleja Transgenic mice and overexpression model of the gene ntrk3 (trkc) based thereon for the study and monitoring of treatments of anxiety, depression and related psychiatric diseases
US6780490B1 (en) 1999-08-06 2004-08-24 Yukadenshi Co., Ltd. Tray for conveying magnetic head for magnetic disk
WO2001025466A1 (en) 1999-10-05 2001-04-12 Oxford Biomedica (Uk) Limited Producer cell for the production of retroviral vectors
US6609020B2 (en) 1999-12-01 2003-08-19 Steven Gill Neurosurgical guide device
US6808873B2 (en) 2000-01-14 2004-10-26 Mitokor, Inc. Screening assays using intramitochondrial calcium
US20060025756A1 (en) 2000-01-19 2006-02-02 Francischelli David E Methods of using high intensity focused ultrasound to form an ablated tissue area
US20050267454A1 (en) 2000-01-19 2005-12-01 Medtronic, Inc. Methods of using high intensity focused ultrasound to form an ablated tissue area containing a plurality of lesions
US20020094516A1 (en) 2000-02-18 2002-07-18 Calos Michele P. Altered recombinases for genome modification
US20080167261A1 (en) 2000-02-18 2008-07-10 Sclimenti Christopher R Altered Recombinases for Genome Modification
US6473639B1 (en) 2000-03-02 2002-10-29 Neuropace, Inc. Neurological event detection procedure using processed display channel based algorithms and devices incorporating these procedures
US6480743B1 (en) 2000-04-05 2002-11-12 Neuropace, Inc. System and method for adaptive brain stimulation
US20020193327A1 (en) 2000-05-01 2002-12-19 The Scripps Research Institute Vectors for occular transduction and use therefor for genetic therapy
US7220240B2 (en) 2000-05-03 2007-05-22 Aspect Medical Systems, Inc. System and method for adaptive drug delivery
US20030103949A1 (en) 2000-05-17 2003-06-05 Carpenter Melissa K. Screening small molecule drugs using neural cells differentiated from human embryonic stem cells
US6551346B2 (en) 2000-05-17 2003-04-22 Kent Crossley Method and apparatus to prevent infections
US20040013645A1 (en) 2000-06-01 2004-01-22 Monahan Paul E. Methods and compounds for controlled release of recombinant parvovirus vectors
US20030088060A1 (en) 2000-07-05 2003-05-08 Benjamin Christopher W Human ion channels
US20060216689A1 (en) 2000-07-10 2006-09-28 Maher Michael P Ion channel assay methods
US6969449B2 (en) 2000-07-10 2005-11-29 Vertex Pharmaceuticals (San Diego) Llc Multi-well plate and electrode assemblies for ion channel assays
US6686193B2 (en) 2000-07-10 2004-02-03 Vertex Pharmaceuticals, Inc. High throughput method and system for screening candidate compounds for activity against target ion channels
US6921413B2 (en) 2000-08-16 2005-07-26 Vanderbilt University Methods and devices for optical stimulation of neural tissues
US6567690B2 (en) 2000-10-16 2003-05-20 Cole Giller Method and apparatus for probe localization in brain matter
US6889085B2 (en) 2000-10-17 2005-05-03 Sony Corporation Method and system for forming an acoustic signal from neural timing difference data
US20050197679A1 (en) 2000-10-17 2005-09-08 Dawson Thomas P. Method and system for forming an acoustic signal from neural timing difference data
US20040267118A1 (en) 2000-10-17 2004-12-30 Sony Corporation/Sony Electronics Inc. Scanning method for applying ultrasonic acoustic data to the human neural cortex
US6729337B2 (en) 2000-10-17 2004-05-04 Sony Corporation Method and system for generating sensory data onto the human neural cortex
US6536440B1 (en) 2000-10-17 2003-03-25 Sony Corporation Method and system for generating sensory data onto the human neural cortex
US20040076613A1 (en) 2000-11-03 2004-04-22 Nicholas Mazarakis Vector system
US6631283B2 (en) 2000-11-15 2003-10-07 Virginia Tech Intellectual Properties, Inc. B/B-like fragment targeting for the purposes of photodynamic therapy and medical imaging
JP2004534508A (ja) 2000-11-16 2004-11-18 リサーチ　ディベロップメント　ファンデーション コルチコトロピン放出因子レセプタ２欠失マウスとその利用
US6506154B1 (en) 2000-11-28 2003-01-14 Insightec-Txsonics, Ltd. Systems and methods for controlling a phased array focused ultrasound system
US20040068202A1 (en) 2000-11-30 2004-04-08 Hans-Axel Hansson System and method for automatic taking of specimens
US20070196838A1 (en) 2000-12-08 2007-08-23 Invitrogen Corporation Methods and compositions for synthesis of nucleic acid molecules using multiple recognition sites
US6489115B2 (en) 2000-12-21 2002-12-03 The Board Of Regents Of The University Of Nebraska Genetic assays for trinucleotide repeat mutations in eukaryotic cells
US6615080B1 (en) 2001-03-29 2003-09-02 John Duncan Unsworth Neuromuscular electrical stimulation of the foot muscles for prevention of deep vein thrombosis and pulmonary embolism
US20050143295A1 (en) 2001-04-04 2005-06-30 Irm Llc Methods for treating drug addiction
US20030097122A1 (en) 2001-04-10 2003-05-22 Ganz Robert A. Apparatus and method for treating atherosclerotic vascular disease through light sterilization
US20020190922A1 (en) 2001-06-16 2002-12-19 Che-Chih Tsao Pattern projection techniques for volumetric 3D displays and 2D displays
US6810285B2 (en) 2001-06-28 2004-10-26 Neuropace, Inc. Seizure sensing and detection using an implantable device
US7144733B2 (en) 2001-08-16 2006-12-05 Sloan-Kettering Institute For Cancer Research Bio-synthetic photostimulators and methods of use
US20030040080A1 (en) 2001-08-16 2003-02-27 Gero Miesenbock Bio-synthetic photostimulators and methods of use
US20030082809A1 (en) 2001-08-23 2003-05-01 Quail Peter H. Universal light-switchable gene promoter system
US6974448B2 (en) 2001-08-30 2005-12-13 Medtronic, Inc. Method for convection enhanced delivery catheter to treat brain and other tumors
US20040073278A1 (en) 2001-09-04 2004-04-15 Freddy Pachys Method of and device for therapeutic illumination of internal organs and tissues
US20060057192A1 (en) 2001-09-28 2006-03-16 Kane Patrick D Localized non-invasive biological modulation system
US7175596B2 (en) 2001-10-29 2007-02-13 Insightec-Txsonics Ltd System and method for sensing and locating disturbances in an energy path of a focused ultrasound system
US20060253177A1 (en) 2001-11-01 2006-11-09 Taboada Luis D Device and method for providing phototherapy to the brain
WO2003040323A2 (en) 2001-11-08 2003-05-15 Children's Medical Center Corporation Bacterial ion channel and a method for screening ion channel modulators
EP1444889A1 (en) 2001-11-14 2004-08-11 Yamanouchi Pharmaceutical Co. Ltd. Transgenic animal
WO2003046141A2 (en) 2001-11-26 2003-06-05 Advanced Cell Technology, Inc. Methods for making and using reprogrammed human somatic cell nuclei and autologous and isogenic human stem cells
US20030104512A1 (en) 2001-11-30 2003-06-05 Freeman Alex R. Biosensors for single cell and multi cell analysis
US20030125719A1 (en) 2001-12-31 2003-07-03 Furnish Simon M. Multi-fiber catheter probe arrangement for tissue analysis or treatment
US6721603B2 (en) 2002-01-25 2004-04-13 Cyberonics, Inc. Nerve stimulation as a treatment for pain
US20030144650A1 (en) 2002-01-29 2003-07-31 Smith Robert F. Integrated wavefront-directed topography-controlled photoablation
US20050107753A1 (en) 2002-02-01 2005-05-19 Ali Rezai Microinfusion device
US20040039312A1 (en) 2002-02-20 2004-02-26 Liposonix, Inc. Ultrasonic treatment and imaging of adipose tissue
US6918872B2 (en) 2002-03-08 2005-07-19 Olympus Corporation Capsule endoscope
US20030232339A1 (en) 2002-04-01 2003-12-18 Youmin Shu Human TRPCC cation channel and uses
US20070135875A1 (en) 2002-04-08 2007-06-14 Ardian, Inc. Methods and apparatus for thermally-induced renal neuromodulation
US7824869B2 (en) 2002-04-11 2010-11-02 Max-Planck-Gesellschaft Zur Foerderung Der Wissenschaften E.V. Use of biological photoreceptors as directly light-activated ion channels
US20050202398A1 (en) 2002-04-11 2005-09-15 Max-Planck-Gesellschaft Zur Forderung Der Wissenschaften E.V. Use of biological photoreceptors as directly light-activated ion channels
WO2003084994A2 (de) 2002-04-11 2003-10-16 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Verwendung von biologischen photorezeptoren als direkt lichtgesteuerte ionenkanäle
US20110092800A1 (en) 2002-04-30 2011-04-21 Seung-Schik Yoo Methods for modifying electrical currents in neuronal circuits
US20030204135A1 (en) 2002-04-30 2003-10-30 Alexander Bystritsky Methods for stimulating neurons
US7298143B2 (en) 2002-05-13 2007-11-20 Koninklijke Philips Electronics N.V. Reduction of susceptibility artifacts in subencoded single-shot magnetic resonance imaging
US20040023203A1 (en) 2002-05-31 2004-02-05 Gero Miesenbock Heterologous stimulus-gated ion channels and methods of using same
WO2003102156A2 (en) 2002-05-31 2003-12-11 Sloan-Kettering Institute For Cancer Research Heterologous stimulus-gated ion channels and methods of using same
US20040015211A1 (en) 2002-06-04 2004-01-22 Nurmikko Arto V. Optically-connected implants and related systems and methods of use
WO2003106486A1 (de) 2002-06-12 2003-12-24 Fraunhofer-Gelellschaft Zur Förderung Der Angewandten Forschung E.V. Pflanzliche proteinpräparate und deren verwendung
US20080065183A1 (en) 2002-06-20 2008-03-13 Advanced Bionics Corporation Vagus nerve stimulation via unidirectional propagation of action potentials
US20040049134A1 (en) 2002-07-02 2004-03-11 Tosaya Carol A. System and methods for treatment of alzheimer's and other deposition-related disorders of the brain
US20050020945A1 (en) 2002-07-02 2005-01-27 Tosaya Carol A. Acoustically-aided cerebrospinal-fluid manipulation for neurodegenerative disease therapy
US20060106543A1 (en) 2002-08-09 2006-05-18 Gustavo Deco Method for analyzing effectiveness of pharmaceutical preparation
US20060167500A1 (en) 2002-08-19 2006-07-27 Bruce Towe Neurostimulator
US20110021270A1 (en) 2002-09-13 2011-01-27 Bally Gaming, Inc. Device verification system and method
WO2004033647A2 (en) 2002-10-10 2004-04-22 Merck & Co., Inc. Assay methods for state-dependent calcium channel agonists/antagonists
US20050058987A1 (en) 2002-11-18 2005-03-17 Pei-Yong Shi Screening for west nile virus antiviral therapy
US20060179501A1 (en) 2002-12-16 2006-08-10 Chan Andrew C Transgenic mice expressing human cd20
US20040122475A1 (en) 2002-12-18 2004-06-24 Myrick Andrew J. Electrochemical neuron systems
US20040216177A1 (en) 2003-04-25 2004-10-28 Otsuka Pharmaceutical Co., Ltd. Congenic rats containing a mutant GPR10 gene
US20070197918A1 (en) 2003-06-02 2007-08-23 Insightec - Image Guided Treatment Ltd. Endo-cavity focused ultrasound transducer
US20050027284A1 (en) 2003-06-19 2005-02-03 Advanced Neuromodulation Systems, Inc. Method of treating depression, mood disorders and anxiety disorders using neuromodulation
US7091500B2 (en) 2003-06-20 2006-08-15 Lucent Technologies Inc. Multi-photon endoscopic imaging system
US20050112759A1 (en) 2003-06-20 2005-05-26 Milica Radisic Application of electrical stimulation for functional tissue engineering in vitro and in vivo
JP2005034073A (ja) 2003-07-16 2005-02-10 Masamitsu Iino ミオシン軽鎖リン酸化の測定用蛍光性プローブ
US20090326603A1 (en) 2003-09-12 2009-12-31 Case Western Reserve University Apparatus for stimulating components in, on, or near the pudendal nerve or its branches to achieve selective physiologic responses
US20050153885A1 (en) 2003-10-08 2005-07-14 Yun Anthony J. Treatment of conditions through modulation of the autonomic nervous system
US20050143790A1 (en) 2003-10-21 2005-06-30 Kipke Daryl R. Intracranial neural interface system
US20050088177A1 (en) 2003-10-22 2005-04-28 Oliver Schreck Method for slice position planning of tomographic measurements, using statistical images
US20060034943A1 (en) 2003-10-31 2006-02-16 Technology Innovations Llc Process for treating a biological organism
US20080119421A1 (en) 2003-10-31 2008-05-22 Jack Tuszynski Process for treating a biological organism
US20070031924A1 (en) 2003-11-21 2007-02-08 The Johns Hopkins University Biomolecule partition motifs and uses thereof
US20050124897A1 (en) 2003-12-03 2005-06-09 Scimed Life Systems, Inc. Apparatus and methods for delivering acoustic energy to body tissue
CN1558222A (zh) 2004-02-03 2004-12-29 复旦大学 生物光敏蛋白-纳米半导体复合光电极的制备方法
US20050240127A1 (en) 2004-03-02 2005-10-27 Ralf Seip Ultrasound phased arrays
US20050215764A1 (en) 2004-03-24 2005-09-29 Tuszynski Jack A Biological polymer with differently charged portions
JP2007530027A (ja) 2004-03-26 2007-11-01 ブリーニ、マリサ 細胞内パラメータを改変することができる分子をスクリーニングするための発光タンパク質プローブを用いて、前記パラメータを検出するための方法
WO2005093429A2 (en) 2004-03-26 2005-10-06 Brini, Marisa Method for the detection of intracellular parameters with luminescent protein probes for the screening of molecules capable of altering said parameters
US20080033569A1 (en) 2004-04-19 2008-02-07 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Bioelectromagnetic interface system
US7313442B2 (en) 2004-04-30 2007-12-25 Advanced Neuromodulation Systems, Inc. Method of treating mood disorders and/or anxiety disorders by brain stimulation
US20050267011A1 (en) 2004-05-24 2005-12-01 The Board Of Trustees Of The Leland Stanford Junior University Coupling of excitation and neurogenesis in neural stem/progenitor cells
US20050279354A1 (en) 2004-06-21 2005-12-22 Harvey Deutsch Structures and Methods for the Joint Delivery of Fluids and Light
US20060057614A1 (en) 2004-08-04 2006-03-16 Nathaniel Heintz Tethering neuropeptides and toxins for modulation of ion channels and receptors
US20060058671A1 (en) 2004-08-11 2006-03-16 Insightec-Image Guided Treatment Ltd Focused ultrasound system with adaptive anatomical aperture shaping
US20060058678A1 (en) 2004-08-26 2006-03-16 Insightec - Image Guided Treatment Ltd. Focused ultrasound system for surrounding a body tissue mass
US20060100679A1 (en) 2004-08-27 2006-05-11 Dimauro Thomas Light-based implants for treating Alzheimer's disease
US7603174B2 (en) 2004-10-21 2009-10-13 Advanced Neuromodulation Systems, Inc. Stimulation of the amygdalohippocampal complex to treat neurological conditions
US7613520B2 (en) 2004-10-21 2009-11-03 Advanced Neuromodulation Systems, Inc. Spinal cord stimulation to treat auditory dysfunction
US20070239080A1 (en) 2004-10-22 2007-10-11 Wolfgang Schaden Methods for promoting nerve regeneration and neuronal growth and elongation
US20060161227A1 (en) 2004-11-12 2006-07-20 Northwestern University Apparatus and methods for optical stimulation of the auditory nerve
US20060155348A1 (en) 2004-11-15 2006-07-13 Decharms Richard C Applications of the stimulation of neural tissue using light
US20060271024A1 (en) 2005-01-25 2006-11-30 Michael Gertner Nasal Cavity Treatment Apparatus
US7686839B2 (en) 2005-01-26 2010-03-30 Lumitex, Inc. Phototherapy treatment devices for applying area lighting to a wound
US20060184069A1 (en) 2005-02-02 2006-08-17 Vaitekunas Jeffrey J Focused ultrasound for pain reduction
US20080020465A1 (en) 2005-02-02 2008-01-24 Malla Padidam Site-specific serine recombinases and methods of their use
JP2006217866A (ja) 2005-02-10 2006-08-24 Tohoku Univ 光感受性を新たに賦与した神経細胞
US20060190044A1 (en) 2005-02-22 2006-08-24 Cardiac Pacemakers, Inc. Cell therapy and neural stimulation for cardiac repair
US20060206172A1 (en) 2005-03-14 2006-09-14 Dimauro Thomas M Red light implant for treating Parkinson's Disease
US20100209352A1 (en) 2005-03-29 2010-08-19 The Trustees Of Columbia University In The City Of Synthesis and conjugation of iron oxide nanoparticles to antibodies for targeting specific cells using fluorescence and mr imaging techniques
US20090319008A1 (en) 2005-03-31 2009-12-24 Esther Mayer Probe device, system and method for photobiomodulation of tissue lining a body cavity
WO2006103678A2 (en) 2005-03-31 2006-10-05 Esther Mayer Probe device, system and method for photobiomodulation of tissue lining a body cavity
JP2006295350A (ja) 2005-04-07 2006-10-26 Sony Corp 撮像装置及び撮像結果の処理方法
US20060236525A1 (en) 2005-04-11 2006-10-26 Jack Sliwa High intensity ultrasound transducers and methods and devices for manufacturing high intensity ultrasound transducers
US20090131837A1 (en) 2005-04-23 2009-05-21 Smith & Nephew, Plc Ultrasound Device
US20060241697A1 (en) 2005-04-25 2006-10-26 Cardiac Pacemakers, Inc. System to provide neural markers for sensed neural activity
US20080290318A1 (en) 2005-04-26 2008-11-27 Van Veggel Franciscus C J M Production of Light from Sol-Gel Derived Thin Films Made with Lanthanide Doped Nanoparticles, and Preparation Thereof
US20090069261A1 (en) 2005-05-02 2009-03-12 Genzyme Corporation Gene therapy for spinal cord disorders
US20080200749A1 (en) 2005-06-15 2008-08-21 Yunfeng Zheng Magnetic Stimulating Circuit For Nervous Centralis System Apparatus, Purpose, and Method Thereof
US20070027443A1 (en) 2005-06-29 2007-02-01 Ondine International, Ltd. Hand piece for the delivery of light and system employing the hand piece
US20100190229A1 (en) 2005-07-22 2010-07-29 Feng Zhang System for optical stimulation of target cells
US20100234273A1 (en) 2005-07-22 2010-09-16 The Board Of Trustees Of The Leland Stanford Junior University Light-activated cation channel and uses thereof
US20070261127A1 (en) 2005-07-22 2007-11-08 Boyden Edward S Light-activated cation channel and uses thereof
US20090088680A1 (en) 2005-07-22 2009-04-02 Alexander Aravanis Optical tissue interface method and apparatus for stimulating cells
US20090099038A1 (en) 2005-07-22 2009-04-16 Karl Deisseroth Cell line, system and method for optical-based screening of ion-channel modulators
US20070054319A1 (en) 2005-07-22 2007-03-08 Boyden Edward S Light-activated cation channel and uses thereof
US8906360B2 (en) * 2005-07-22 2014-12-09 The Board Of Trustees Of The Leland Stanford Junior University Light-activated cation channel and uses thereof
US8926959B2 (en) 2005-07-22 2015-01-06 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US20080085265A1 (en) 2005-07-22 2008-04-10 Schneider M B System for optical stimulation of target cells
WO2007024391A2 (en) 2005-07-22 2007-03-01 The Board Of Trustees Of The Leland Stanford Junior University Light-activated cation channel and uses thereof
US20070060984A1 (en) 2005-09-09 2007-03-15 Webb James S Apparatus and method for optical stimulation of nerves and other animal tissue
US20070060915A1 (en) 2005-09-15 2007-03-15 Cannuflow, Inc. Arthroscopic surgical temperature control system
US20070220628A1 (en) 2005-12-21 2007-09-20 Pioneer Hi-Bred International, Inc. Methods and compositions for in planta production of inverted repeats
US7610100B2 (en) 2005-12-30 2009-10-27 Boston Scientific Neuromodulation Corporation Methods and systems for treating osteoarthritis
US20070156180A1 (en) 2005-12-30 2007-07-05 Jaax Kristen N Methods and systems for treating osteoarthritis
US20070191906A1 (en) 2006-02-13 2007-08-16 Anand Iyer Method and apparatus for selective nerve stimulation
US20070219600A1 (en) 2006-03-17 2007-09-20 Michael Gertner Devices and methods for targeted nasal phototherapy
US20070282404A1 (en) 2006-04-10 2007-12-06 University Of Rochester Side-firing linear optic array for interstitial optical therapy and monitoring using compact helical geometry
US20070239210A1 (en) 2006-04-10 2007-10-11 Imad Libbus System and method for closed-loop neural stimulation
US20070253995A1 (en) 2006-04-28 2007-11-01 Medtronic, Inc. Drug Delivery Methods and Devices for Treating Stress Urinary Incontinence
US20070260295A1 (en) 2006-05-03 2007-11-08 Light Sciences Corporation Light transmission system for photoreactive therapy
WO2007131180A2 (en) 2006-05-04 2007-11-15 Wayne State University Restoration of visual responses by in vivo delivery of rhodopsin nucleic acids
US20080176076A1 (en) 2006-05-11 2008-07-24 University Of Victoria Innovation And Development Corporation Functionalized lanthanide rich nanoparticles and use thereof
US20080262411A1 (en) 2006-06-02 2008-10-23 Dobak John D Dynamic nerve stimulation in combination with other eating disorder treatment modalities
US20080046053A1 (en) 2006-06-19 2008-02-21 Wagner Timothy A Apparatus and method for stimulation of biological tissue
EP1873566A2 (en) 2006-06-26 2008-01-02 Osram Sylvania, Inc. Light emitting diode with light guide assembly
JP2008010422A (ja) 2006-06-26 2008-01-17 Osram Sylvania Inc 直視レンズ付きの発光ダイオード
US20070295978A1 (en) 2006-06-26 2007-12-27 Coushaine Charles M Light emitting diode with direct view optic
WO2008014382A2 (en) 2006-07-26 2008-01-31 Case Western Reserve University System and method for controlling g-protein coupled receptor pathways
US20080027505A1 (en) 2006-07-26 2008-01-31 G&L Consulting, Llc System and method for treatment of headaches
US20100009444A1 (en) 2006-07-26 2010-01-14 Stefan Herlitze System and method for controlling g-protein coupled receptor pathways
US20080088258A1 (en) 2006-07-28 2008-04-17 Stmicroelectronics Asia Pacific Pte Ltd Addressable LED architecture
US20080051673A1 (en) 2006-08-17 2008-02-28 Xuan Kong Motor unit number estimation (MUNE) for the assessment of neuromuscular function
US20080125836A1 (en) 2006-08-24 2008-05-29 Jackson Streeter Low level light therapy for enhancement of neurologic function of a patient affected by parkinson's disease
US20080060088A1 (en) 2006-09-01 2008-03-06 Heesup Shin Phospholipase c beta1 (plcbeta1) knockout mice as a model system for testing schizophrenia drugs
US20080065158A1 (en) 2006-09-07 2008-03-13 Omry Ben-Ezra Techniques for reducing pain associated with nerve stimulation
US20080077200A1 (en) 2006-09-21 2008-03-27 Aculight Corporation Apparatus and method for stimulation of nerves and automated control of surgical instruments
US7988688B2 (en) 2006-09-21 2011-08-02 Lockheed Martin Corporation Miniature apparatus and method for optical stimulation of nerves and other animal tissue
US20080103551A1 (en) 2006-10-30 2008-05-01 Javaid Masoud Implantable Medical Device with Variable Data Retransmission Characteristics Based Upon Data Type
US20100021982A1 (en) 2006-12-06 2010-01-28 Stefan Herlitze Light-sensitive constructs for inducing cell death and cell signaling
US20100146645A1 (en) 2006-12-12 2010-06-10 Eero Vasar Transgenic animal model for modelling pathological anxiety, a method for identifying compounds for treatment of diseases or disorders caused by pathological anxiety and a method for using wfs1 protein as a target for identifying effective compounds against pathological anxiety
WO2008086470A1 (en) 2007-01-10 2008-07-17 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US8398692B2 (en) 2007-01-10 2013-03-19 The Board Of Trustees Of The Leland Stanford Junior University System for optical stimulation of target cells
US20100145418A1 (en) 2007-01-10 2010-06-10 Feng Zhang System for optical stimulation of target cells
US7883536B1 (en) 2007-01-19 2011-02-08 Lockheed Martin Corporation Hybrid optical-electrical probes
US20080227139A1 (en) 2007-02-14 2008-09-18 Karl Deisseroth System, method and applications involving identification of biological circuits such as neurological characteristics
US8401609B2 (en) 2007-02-14 2013-03-19 The Board Of Trustees Of The Leland Stanford Junior University System, method and applications involving identification of biological circuits such as neurological characteristics
WO2008106694A2 (en) 2007-03-01 2008-09-04 The Board Of Trustees Of The Leland Stanford Junior University Systems, methods and compositions for optical stimulation of target cells
US20110301529A1 (en) 2007-03-01 2011-12-08 The Board Of Trustees Of The Leland Stanford Junior University Systems, methods and compositions for optical stimulation of target cells
US20090093403A1 (en) 2007-03-01 2009-04-09 Feng Zhang Systems, methods and compositions for optical stimulation of target cells
US20080221452A1 (en) 2007-03-09 2008-09-11 Philip Chidi Njemanze Method for inducing and monitoring long-term potentiation and long-term depression using transcranial doppler ultrasound device in head-down bed rest
US20080228244A1 (en) 2007-03-16 2008-09-18 Old Dominion University Modulation of neuromuscular functions with ultrashort electrical pulses
US20080287821A1 (en) 2007-03-30 2008-11-20 Searete Llc, A Limited Liability Corporation Of The State Of Delaware Computational user-health testing
US8386312B2 (en) 2007-05-01 2013-02-26 The Nielsen Company (Us), Llc Neuro-informatics repository system
US20090030930A1 (en) 2007-05-01 2009-01-29 Neurofocus Inc. Neuro-informatics repository system
US20090148861A1 (en) 2007-06-20 2009-06-11 The Salk Institute Kir channel modulators
WO2009025819A1 (en) 2007-08-22 2009-02-26 Cardiac Pacemakers, Inc. Optical depolarization of cardiac tissue
US20090118800A1 (en) 2007-10-31 2009-05-07 Karl Deisseroth Implantable optical stimulators
US20090112133A1 (en) 2007-10-31 2009-04-30 Karl Deisseroth Device and method for non-invasive neuromodulation
US20090157145A1 (en) 2007-11-26 2009-06-18 Lawrence Cauller Transfer Coil Architecture
WO2009072123A2 (en) 2007-12-06 2009-06-11 Technion Research & Development Foundation Ltd. Method and system for optical stimulation of neurons
US20090268511A1 (en) 2008-01-16 2009-10-29 University Of Connecticut Bacteriorhodopsin Protein Variants and Methods of Use for Long Term Data Storage
US20090254134A1 (en) 2008-02-04 2009-10-08 Medtrode Inc. Hybrid ultrasound/electrode device for neural stimulation and recording
WO2009119782A1 (ja) 2008-03-24 2009-10-01 国立大学法人東北大学 改変された光受容体チャネル型ロドプシンタンパク質
US20100016783A1 (en) 2008-04-04 2010-01-21 Duke University Non-invasive systems and methods for in-situ photobiomodulation
US8815582B2 (en) 2008-04-23 2014-08-26 The Board Of Trustees Of The Leland Stanford Junior University Mammalian cell expressing Volvox carteri light-activated ion channel protein (VChR1)
WO2009131837A2 (en) 2008-04-23 2009-10-29 The Board Of Trustees Of The Leland Stanford Junior University. Systems, methods and compositions for optical stimulation of target cells
US20110105998A1 (en) 2008-04-23 2011-05-05 The Board Of Trustees Of The Leland Stanford Junio Systems, methods and compositions for optical stimulation of target cells
WO2010011404A2 (en) 2008-05-20 2010-01-28 Eos Neuroscience, Inc. Vectors for delivery of light-sensitive proteins and methods of use
US20120093772A1 (en) 2008-05-20 2012-04-19 Alan Horsager Vectors for delivery of light sensitive proteins and methods of use
CN102076866A (zh) 2008-05-29 2011-05-25 利兰·斯坦福青年大学托管委员会 光学控制第二信使的细胞系、系统和方法
US20110112179A1 (en) 2008-05-29 2011-05-12 Airan Raag D Cell line, system and method for optical control of secondary messengers
WO2009148946A2 (en) 2008-05-29 2009-12-10 The Board Of Trustees Of The Leland Stanford Junior University Cell line, system and method for optical control of secondary messengers
US20090306474A1 (en) 2008-06-09 2009-12-10 Capso Vision, Inc. In vivo camera with multiple sources to illuminate tissue at different distances
US20110159562A1 (en) 2008-06-17 2011-06-30 Karl Deisseroth Apparatus and methods for controlling cellular development
US20110172653A1 (en) 2008-06-17 2011-07-14 Schneider M Bret Methods, systems and devices for optical stimulation of target cells using an optical transmission element
US20110166632A1 (en) 2008-07-08 2011-07-07 Delp Scott L Materials and approaches for optical stimulation of the peripheral nervous system
WO2010006049A1 (en) 2008-07-08 2010-01-14 The Board Of Trustees Of The Leland Stanford Junior University Materials and approaches for optical stimulation of the peripheral nervous system
US20110233046A1 (en) 2008-09-25 2011-09-29 The Trustees Of Columbia University In The City Of New York Devices, apparatus and method for providing photostimulation and imaging of structures
US9458208B2 (en) 2008-11-14 2016-10-04 The Board Of Trustees Of The Leland Stanford Junior University Optically-based stimulation of target cells and modifications thereto
US20110311489A1 (en) 2008-11-14 2011-12-22 Karl Deisseroth Optically-based stimulation of target cells and modifications thereto
JP2012508581A (ja) 2008-11-14 2012-04-12 ボード オブ トラスティーズ オブ ザ レランド スタンフォード ジュニア ユニバーシティ 標的細胞の光学に基づく刺激及びそれに対する改変
WO2010056970A2 (en) 2008-11-14 2010-05-20 The Board Of Trustees Of The Leland Stanford Junior University Optically-based stimulation of target cells and modifications thereto
US20110165681A1 (en) 2009-02-26 2011-07-07 Massachusetts Institute Of Technology Light-Activated Proton Pumps and Applications Thereof
US20130144359A1 (en) 2009-03-24 2013-06-06 Eyad Kishawi Pain management with stimulation subthreshold to paresthesia
JP2010227537A (ja) 2009-03-25 2010-10-14 Korea Inst Of Science & Technology 光刺激装置
WO2010123993A1 (en) 2009-04-21 2010-10-28 Tuan Vo-Dinh Non-invasive energy upconversion methods and systems for in-situ photobiomodulation
WO2011005978A2 (en) 2009-07-08 2011-01-13 Duke University Methods of manipulating cell signaling
US20110112463A1 (en) 2009-11-12 2011-05-12 Jerry Silver Compositions and methods for treating a neuronal injury or neuronal disorders
US20110125077A1 (en) 2009-11-25 2011-05-26 Medtronic, Inc. Optical stimulation therapy
WO2011066320A2 (en) 2009-11-25 2011-06-03 Medtronic, Inc. Optical stimulation therapy
US20110125078A1 (en) 2009-11-25 2011-05-26 Medtronic, Inc. Optical stimulation therapy
WO2011106783A2 (en) 2010-02-26 2011-09-01 Cornell University Retina prosthesis
US20130019325A1 (en) 2010-03-17 2013-01-17 Karl Deisseroth Light-Sensitive Ion-Passing Molecules
US9079940B2 (en) 2010-03-17 2015-07-14 The Board Of Trustees Of The Leland Stanford Junior University Light-sensitive ion-passing molecules
WO2011116238A2 (en) 2010-03-17 2011-09-22 The Board Of Trustees Of The Leland Stanford Junior University. Light-sensitive ion-passing molecules
US9604073B2 (en) 2010-03-17 2017-03-28 The Board Of Trustees Of The Leland Stanford Junior University Light-sensitive ion-passing molecules
WO2011127088A2 (en) 2010-04-05 2011-10-13 Eos Neuroscience, Inc. Methods and compositions for decreasing chronic pain
US20130286181A1 (en) 2010-06-14 2013-10-31 Howard Hughes Medical Institute Structured plane illumination microscopy
US9057734B2 (en) 2010-08-23 2015-06-16 President And Fellows Of Harvard College Optogenetic probes for measuring membrane potential
WO2012032103A1 (en) 2010-09-08 2012-03-15 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Mutant channelrhodopsin 2
CN103313752A (zh) 2010-11-05 2013-09-18 斯坦福大学托管董事会 用于光遗传学方法的光的上转换
CN103476456A (zh) 2010-11-05 2013-12-25 斯坦福大学托管董事会 奖赏相关行为的光遗传学控制
WO2012061676A1 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Light-activated chimeric opsins and methods of using the same
WO2012061688A1 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic control of reward-related behaviors
WO2012061690A2 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Optically-controlled cns dysfunction
WO2012061684A1 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Upconversion of light for use in optogenetic methods
WO2012061681A1 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University. Control and characterization of memory function
US9522288B2 (en) 2010-11-05 2016-12-20 The Board Of Trustees Of The Leland Stanford Junior University Upconversion of light for use in optogenetic methods
WO2012061741A2 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University. Control and characterization of psychotic states
US9175095B2 (en) 2010-11-05 2015-11-03 The Board Of Trustees Of The Leland Stanford Junior University Light-activated chimeric opsins and methods of using the same
WO2012061744A2 (en) 2010-11-05 2012-05-10 The Board Of Trustees Of The Leland Stanford Junior University Stabilized step function opsin proteins and methods of using the same
US20120121542A1 (en) 2010-11-13 2012-05-17 Amy Chuong Red-shifted opsin molecules and uses thereof
US20120165904A1 (en) 2010-11-22 2012-06-28 Jin Hyung Lee Optogenetic magnetic resonance imaging
US8696722B2 (en) 2010-11-22 2014-04-15 The Board Of Trustees Of The Leland Stanford Junior University Optogenetic magnetic resonance imaging
WO2012106407A2 (en) 2011-02-01 2012-08-09 The University Of Vermont And State Agricultural College Diagnostic and therapeutic methods and products related to anxiety disorders
US20120253261A1 (en) 2011-03-29 2012-10-04 Medtronic, Inc. Systems and methods for optogenetic modulation of cells within a patient
WO2012134704A2 (en) 2011-03-29 2012-10-04 Medtronic, Inc. Systems and methods for optogenetic modulation of cells within a patient
WO2013003557A1 (en) 2011-06-28 2013-01-03 University Of Rochester Photoactivatable receptors and their uses
US20130030275A1 (en) 2011-07-25 2013-01-31 Seymour John P Opto-electrical device and method for artifact reduction
WO2013016486A1 (en) 2011-07-27 2013-01-31 The Board Of Trustees Of The University Of Illinois Nanopore sensors for biomolecular characterization
WO2013090356A2 (en) 2011-12-16 2013-06-20 The Board Of Trustees Of The Leland Stanford Junior University Opsin polypeptides and methods of use thereof
WO2013126521A1 (en) 2012-02-21 2013-08-29 The Board Of Trustees Of The Leland Stanford Junior University Compositions and methods for treating neurogenic disorders of the pelvic floor
WO2013126762A1 (en) 2012-02-23 2013-08-29 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Office Of Technology Transfer, National Institutes Of Health Multi-focal structured illumination microscopy systems and methods
WO2013142196A1 (en) 2012-03-20 2013-09-26 The Board Of Trustees Of The Leland Stanford Junior University Non-human animal models of depression and methods of use thereof
WO2014081449A1 (en) 2012-11-21 2014-05-30 Circuit Therapeutics, Inc. System and method for optogenetic therapy
WO2014117079A1 (en) 2013-01-25 2014-07-31 The Trustees Of Columbia University In The City Of New York Depth of field 3d imaging slm microscope
US20150112411A1 (en) 2013-10-18 2015-04-23 Varaya Photoceuticals, Llc High powered light emitting diode photobiology compositions, methods and systems
WO2016019075A1 (en) 2014-07-29 2016-02-04 Circuit Therapeutics, Inc. System and method for optogenetic therapy

Non-Patent Citations (531)

* Cited by examiner, † Cited by third party
Title
"N. pharaonis halorhodopsin (hop) gene, complete cds.", XP002704883, retrieved from EBI accession No. EMBL: J05199. Database accession No. J05199. Nov. 22, 1990.
"Subname: Fluu=Bacteriorhodopsin"; XP002704863, retrieved from EBI accession No. UNIPROT: B0R5N9. Database accession No. B0R5N9. Apr. 8, 2008.
[No Authors Listed] "Two bright new faces in gene therapy," Nature Biotechnology, 1996, vol. 14: p. 556.
"SubName: Full=Channelrhodopsin-1", retrieved from EBI accession No. UNIPROT: B4Y103. Database accession No. B4Y103. Sep. 23, 2008.
Abbott, et al.; "Photostimulation of Retrotrapezoid Nucleus Phox2b-Expressing Neurons In Vivo Produces Long-Lasting Activation of Breathing in Rats"; The Journal of Neuroscience; vol. 29, No. 18, pp. 5806-5819 (May 6, 2009).
Adamantidis, et al., "Optogenetic Interrogation of Dopaminergic Modulation of the Multiple Phases of Reward-Seeking Behavior", J. Neurosci, 2011, vol. 31, No. 30, pp. 10829-10835.
Aebischer, et al. "Long-Term Cross-Species Brain Transplantation of a Polymer-Encapsulated Dopamine-Secreting Cell Line", Experimental Neurology, 1991, vol. 111, pp. 269-275.
Ageta-Ishihara et al., "Chronic overload of SEPT4, a parkin substrate that aggregates in Parkinson's disease, cause behavioral alterations but not neurodegeneration in mice", Molecular Brain, 2013, vol. 6, 14 pages.
Ahmad, et al. "The Drosophila rhodopsin cytoplasmic tail domain is required for maintenance of rhabdomere structure." The FASEB Journal, 2007, vol. 21, p. 449-455.
Airan, et al., "Temporally Precise in vivo Control of Intracellular Signaling", 2009, Nature, vol. 458, No. 7241, pp. 1025-1029.
Airan, et al.; "Integration of light-controlled neuronal firing and fast circuit imaging"; Current Opinion in Neurobiology; vol. 17, pp. 587-592 (2007).
Akirav, et al. "The role of the medial prefrontal cortex-amygdala circuit in stress effects on the extinction of fear", Neural Plasticity, 2007: vol. 2007 Article ID:30873, pp. 1-11.
Ali; "Gene and stem cell therapy for retinal disorders"; vision-research.en—The Gateway to European Vision Research; accessed from http://www.vision-research.eu/index.php?id=696, 10 pages (accessed Jul. 24, 2015).
Alilain, et al.; "Light-Induced Rescue of Breathing after Spinal Cord Injury"; The Journal of Neuroscience; vol. 28, No. 46, pp. 11862-11870 (Nov. 12, 2008).
Ang, et at. "Hippocampal CA1 Circuitry Dynamically Gates Direct Cortical Inputs Preferentially at Theta Frequencies." The Journal of Neurosurgery, 2005, vol. 25, No. 42, pp. 9567-9580.
Araki, et al. "Site-Directed Integration of the cre Gene Mediated by Cre Recombinase Using a Combination of Mutant lox Sites", Nucleic Acids Research, 2002, vol. 30, No. 19, pp. 1-8.
Aravanis, et al. "An optical neural interface: in vivo control of rodent motor cortex with integrated fiberoptic and optogenetic technology," J. Neural. Eng., 2007, vol. 4(3):S143-S156.
Arenkiel, et al. "In vivo light-induced activation of neural circuitry in transgenic mice expressing Channelrhodopsin-2", Neuron, 2007, 54:205-218.
Argos, et al. "The integrase family of site-specific recombinases: regional similarities and global diversity", The EMBO Journal, 1986, vol. 5, No. 2, pp. 433-440.
Asano, et al.; "Optically Controlled Contraction of Photosensitive Skeletal Muscle Cells"; Biotechnology & Bioengineering; vol. 109, No. 1, pp. 199-204 (Jan. 2012).
Axoclamp-28 Microelectrode claim theory and operation. Accessed from https://physics.ucsd.edu/neurophysics/Manuals/Axon%20Instruments/Axoclamp-2B_Manual.pdf on Dec. 12, 2014.
Azizgolshani, et al.; "Reconstituted plant viral capsids can release genes to mammalian cells"; Virology; vol. 441, No. 1, pp. 12-17 (2013).
Babin et al., "Zebrafish Models of Human Motor Neuron Diseases: Advantages and Limitations", Progress in Neurobiology (2014), 118:36-58.
Balint, et al., "The Nitrate Transporting Photochemical Reaction Cycle of the Pharaonis Halorhodopsin", Biophysical Journal, 2004, vol. 86, pp. 1655-1663.
Bamberg et al. "Light-driven proton or chloride pumping by halorhodopsin." Proc. Natl. Academy Science USA, 1993, vol. 90, No. 2, p. 639-643.
Banghart, et al. "Light-activated ion channels for remote control of neuronal firing". Nature Neuroscience, 2004, vol. 7, No. 12 pp. 1381-1386.
Barchet, et al.; "Challenges and opportunities in CNS delivery of therapeutics for neurodegenerative diseases"; Expert Opinion on Drug Delivery; vol. 6, No. 3, pp. 211-225 (Mar. 16, 2009).
Basil et al. "Is There Evidence for Effectiveness of Transcranial Magnetic Stimulation in the Treatment of Psychiatric Disorders?" Psychiatry, 2005, pp. 64-69.
Bebbington et al., The use of vectors based on gene amplification for the expression of cloned genes in mammalian cells in "DNA cloning" vol. 3, Academic Press, New York, 1987.
Benabid "Future strategies to restore brain functions," Conference proceedings from Medicine Meets Millennium: World Congress of Medicine and Health, 2000, 6 pages.
Benoist et al. "In vivo sequence requirements of the SV40 early promotor region" Nature (London), 1981, vol. 290(5804): pp. 304-310.
Berges et al., "Transduction of Brain by Herpes Simplex Virus Vectors", Molecular Therapy, 2007, vol. 15, No. 1: pp. 20-29.
Berke, et al. "Addiction, Dopamine, and the Molecular Mechanisms of Memory", Molecular Plasticity, 2000, vol. 25: pp. 515-532.
Berlanga, et a.; "Cholinergic Interneurons of the Nucleus Accumbens and Dorsal Striatum are Activated by the Self-Administration of Cocaine"; Neuroscience; vol. 120, pp. 1149-1156 (2003).
Berndt et al. "Bi-stable neural state switches", Nature Neuroscience, 2009, vol. 12, No. 2: pp. 229-234.
Berndt et al., "Structure-Guided Transformation of Channelrhodopsin into a Light-Activated Chloride Channel", Science (Apr. 2014), 344(6182):420-424.
Berridge et al., "The Versatility and Universality of Calcium Signaling", Nature Reviews: Molecular Cell Biology, 2000, vol. 1: pp. 11-21.
Bi, et al. "Ectopic Expression of a Microbial-Type Rhodopsin Restores Visual Responses in Mice with Photoreceptor Degeneration", Neuron, 2006, vol. 50, No. 1: pp. 23-33.
Bi, et al. "Synaptic Modifications in Cultured Hippocampal Neurons: Dependence on Spike Timing, Synaptic Strength, and Postsynaptic Cell Type", Journal of Neuroscience, 1998, vol. 18, No. 24: pp. 10464-1 0472.
Bibel, et al.; "Differentiation of mouse embryonic stem cells into a defined neuronal lineage"; Nature Neuroscience; vol. 7, No. 9, pp. 1033-1009 (Sep. 2004).
Blomer et al., "Highly Efficient and Sustained Gene Transfer in Adult Neurons with Lentivirus Vector", Journal of Virology,1997, vol. 71, No. 9: pp. 6641-6649.
Bocquet et al. "A prokaryotic proton-gated ion channel from the nicotinic acetylcholine receptor family." Nature Letters, 2007, vol. 445, p. 116-119.
Bowers, et al.; "Genetic therapy for the nervous system"; Human Molecular Genetics; vol. 20, No. 1, pp. R28-R41 (2011).
Boyden, et al. "Millisecond-timescale, genetically targeted optical control of neural activity" Nature Neuroscience, 2005, vol. 8, No. 9: pp. 1263-1268.
Boyden, et al.; "A history of optogenetics: the development of tools for controlling brain circuits with light"; F1000 Biology Reports; vol. 3, No. 11, 12 pages (May 3, 2011).
Braun, "Two Light-activated Conductances in the Eye of the Green Alga Volvox carteri", 1999, Biophys J., vol. 76, No. 3, pp. 1668-1678.
Brewin (2011) Annu. Rev. Clin. Psychol., vol. 7, 203-227, Table I. *
Brewin; "The Nature and Significance of Memory Disturbance in Posttraumatic Stress Disorder"; Ann. Rev. Clin. Psychol.; vol. 7, pp. 203-227 (2011).
Brinton, et al. "Preclinical analyses of the therapeutic potential of allopregnanolone to promote neurogenesis in vitro and in vivo in transgenic mouse model of Alzheimer's disease." Current Alzheimer Research, 2006, vol. 3, No. 1: pp. 11-17.
Brosenitsch et al, "Physiological Patterns of Electrical Stimulation Can Induce Neuronal Gene Expression by Activating N-Type Calcium Channels," Journal of Neuroscience, 2001, vol. 21, No. 8, pp. 2571-2579.
Brown, et al. "Long-term potentiation induced by θ frequency stimulation is regulated by a protein phosphate-operated gate." The Journal of Neuroscience, 2000, vol. 20, No. 21, pp. 7880-7887.
Bruegmann, et al.; "Optogenetic control of heart muscle in vitro and in vivo"; Nature Methods; vol. 7, No. 11, pp. 897-900(Nov. 2010).
Bruegmann, et al.; "Optogenetics in cardiovascular research: a new tool for light-induced depolarization of cardiomyocytes and vascular smooth muscle cells in vitro and in vivo"; European Heart Journal; vol. 32, No. Suppl . 1, p. 997 (Aug. 2011).
Callaway, et al. "Photostimulation using caged glutamate reveals functional circuitry in living brain slices", Proc. Natl. Acad. Sci. USA., 1993, vol. 90: pp. 7661-7665.
Campagnola et al. "Fiber-coupled light-emitting diode for localized photostimulation of neurons expressing channelrhodopsin-2." Journal of Neuroscience Methods , 2008, vol. 169, Issue 1. Abstract only.
Cannon, et al.; "Endophenotypes in the Genetic Analyses of Mental Disorders"; Annu. Rev. Clin. Psychol.; vol. 2, pp. 267-290 (2006).
Cardin, et al. "Driving Fast spiking Cells Induces Gamma Rhythm and Controls Sensory Responses", 2009, Nature, vol. 459, vol. 7247, pp. 663-667.
Cardin, et al.; "Targeted optogenetic stimulation and recording of neurons in vivo using cell-type-specific expression of Channelrhodopsin-2"; Nature Protocols; vol. 5, No. 2, pp. 247-254 (2010).
Caro, et al.; "Engineering of an Artificial Light-Modulated Potassium Channel"; PLoS One; vol. 7, Issue 8, e43766 (Aug. 2012).
Castagne, et al.; "Rodent Models of Depression: Forced Swim and Tail Suspension Behavioral Despair Tests in Rats and Mice"; Current Protocols in Pharmacology; Supp. 49, Unit 5.8.1-5.8.14 (Jun. 2010).
Cazillis et al., "VIP and PACAP induce selective neuronal differentiation of mouse embryonic stem cells", Eur J Neurosci, 2004, 19(4):798-808.
Cenatiempo "Prokaryotic gene expression in vitro: transcription-translation coupled systems", Biochimie, 1986, vol. 68(4): pp. 505-515.
Chamanzar, et al.; "Deep Tissue Targeted Near-infrared Optogenetic Stimulation using Fully Implantable Upconverting Light Bulbs"; 2015 37th Annual International Conference of the IEEE Engineering in Medicine and Biology Society (EMBC), IEEE; doi: 10.1109/EMBC.2015.7318488, pp. 821-824 (Aug. 25, 2015).
Chinta, et al.; "Dopaminergic neurons"; The International Journal of Biochemistry & Cell Biology; vol. 37, pp. 942-946 (2005).
Chow et al., "Optogenetics and Translational Medicine", Science Translational Medicine (Mar. 2013), 5(177):177ps5.
Chow, et al.; "High-performance genetically targetable optical neural silencing by light-driven proton pumps"; Nature; vol. 463, pp. 98-102 (Jan. 7, 2010).
Clark, et al.; "A future for transgenic livestock"; Nature Reviews Genetics; vol. 4, No. 10, pp. 825-833 (Oct. 2003).
Claudio et al. "Nucleotide and deduced amino acid sequences of Torpedo californica acetylcholine receptor gamma subunit." PNAS USA,1983, vol. 80, p. 1111-1115.
Coleman, et al.; "Assessing Anxiety in Nonhuman Primates"; Ilar Journal; vol. 55, No. 2, pp. 333-346 (2014).
Collingridge et al. "Inhibitory post-synaptic currents in rat hippocampal CA1 neurones." J. Physiol., 1984, vol. 356, pp. 551-564.
Covington, et al. "Antidepressant Effect of Optogenetic Stimulation of the Medial Prefrontal Cortex." Journal of Neuroscience, 2010, vol. 30(48), pp. 16082-16090.
Cowan et al., "Targeting gene expression to endothelium in transgenic animals: a comparison of the human ICAM-2, PECAM-1, and endoglin promoters", Xenotransplantation, 2003, vol. 10, pp. 223-231.
Crouse, et al. "Expression and amplification of engineered mouse dihydrofolate reductase minigenes" Mol. Cell. Biol. , 1983, vol. 3(2): pp. 257-266.
Cucchiaro et al., "Electron-Microsoft Analysis of Synaptic Input from the Perigeniculate Nucleus to A-Lamine of the Lateral Geniculate Nucleus in Cats", The Journal of Comparitive Neurology, 1991, vol. 310, pp. 316-336.
Cucchiaro et al., "Phaseolus vulgaris leucoagglutinin (PHA-L): a neuroanatomical tracer for electron microscopic analysis of synaptic circuitry in the cat's dorsal lateral geniculate nucleus" J. Electron. Microsc. Tech., 1990, 15 (4):352-368.
Cui, et al., "Electrochemical deposition and characterization of conducting polymer polypyrrole/PSS on multichannel neural probes," Sensors and Actuators, 2001, vol. 93(1): pp. 8-18.
Dalva, et al. "Rearrangements of Synaptic Connections in Visual Cortex Revealed by Laser Photostimulation", Science, 1994,vol. 265, pp. 255-258.
Daniel, et al.; "Stress Modulation of Opposing Circuits in the Bed Nucleus of the Stria Terminalis"; Neuropsychopharmacology Reviews; vol. 41, pp. 103-125 (2016).
DATABASE EMBL [online] "N.pharaonis halorhodopsin (hop) gene, complete cds.", XP002704883, retrieved from EBI
DATABASE UniProt [online] "SubName: Full=Bacteriorhodopsin;", XP002704863, retrieved from EBI
DATABASE UniProt [online] 1 April 1990 (1990-04-01), LANYI J K, ET AL: "RecName: Full=Halorhodopsin; Short=HR; AltName: Full=NpHR;", XP002704922, retrieved from EBI
Date, et al. "Grafting of Encapsulated Dopamine-Secreting Cells in Parkinson's Disease: Long-Term Primate Study", Cell Transplant, 2000, vol. 9, pp. 705-709.
Davidson, et al.; "Viral Vectors for Gene Delivery to the Nervous System"; Nature Reviews Neuroscience; vol. 4, pp. 353-364 (May 2003).
Davis; "The many faces of epidermal growth factor repeats," The New Biologist; vol. 2, No. 5, pp. 410-419 (1990).
Day, et al.; "The Nucleus Accumbens and Pavlovian Reward Learning"; Neuroscientist; vol. 13, No. 2, pp. 148-159 (Apr. 2007).
De Foubert et al. "Fluoxetine-Induced Change in Rat Brain Expression of Brain-Derived Neurotrophic Factor Varies Depending on Length of Treatment," Neuroscience, 2004, vol. 128, pp. 597-604.
De Palma, et al.; "In Vivo Targeting of Tumor Endothelial Cells by Systemic Delivery of Lentiviral Vectors"; Human Gene Therapy; vol. 14, pp. 1193-1206 (Aug. 10, 2003).
Dederen, et al. "Retrograde neuronal tracing with cholera toxin B subunit: comparison of three different visualization methods", Histochemical Journal, 1994, vol. 26, pp. 856-862.
Definition of Implant; Merriam-Webster Dictionary; retrieved Nov. 7, 2016 (http://www.merriam-webster.com/dictionary/implant).
Definition of integral. Merriam-Webster Dictionary, retrieved on Mar. 20, 2017; Retrieved from the internet: <http://www.merriam-webster.com/dictionary/integral>.
Definition of Psychosis (2015).
Deisseroth "Next-generation optical technologies for illuminating genetically targeted brain circuits," The Journal of Neuroscience, 2006, vol. 26, No. 41, pp. 10380-10386.
Deisseroth et al., "Excitation-neurogenesis Coupling in Adult Neural Stem/Progenitor Cells", 2004, Neuron, vol. 42, pp. 535-552.
Deisseroth et al., "Signaling from Synapse to Nucleus: Postsynaptic CREB Phosphorylation During Multiple Forms of Hippocampal Synaptic Plasticity", Neuron, 1996, vol. 16, pp. 89-101.
Deisseroth et al., "Signaling from Synapse to Nucleus: the logic Behind the Mechanisms", Currrent Opinion in Neurobiology, 2003, vol. 13, pp. 354-65.
Deisseroth et al., "Translocation of Calmodulin to the Nucleus Supports CREB Phosphorylation in Hippocampal Neurons", Nature, 1998, vol. 392, pp. 198-202.
Deisseroth, et al., "Controlling the Brain with Light", Scientific American, 2010, vol. 303, pp. 48-55.
Delaney et al., "Evidence for a long-lived 13-cis-containing intermediate in the photocycle of the leu 93 → ala bacteriorhodopsin mutant", J. Physical Chemistry B, 1997, vol. 101, No. 29, pp. 5619-5621.
Denk, W., et al. "Anatomical and functional imaging of neurons using 2-photon laser scanning microscopy", Journal of Neuroscience Methods, 1994, vol. 54, pp. 151-162.
Deonarain; "Ligand-targeted receptor-mediated vectors for gene delivery"; Exp. Opin. Ther. Patents; vol. 8, No. 1, pp. 53-69 (1998).
Ditterich, et al. "Microstimulation of visual cortex affects the speed of perceptual decisions", 2003, Nature Neuroscience, vol. 6, No. 8, pp. 891-898.
Dittgen, et al. "Lentivirus-based genetic manipulations of cortical neurons and their optical and electrophysiological monitoring in vivo", PNAS, 2004, vol. 101, No. 52, pp. 18206-18211.
Do Carmo, et al.; "Modeling Alzheimer's disease in transgenic rats"; Molecular Neurodegeneration; vol. 8, No. 37, 11 pages (2013).
Douglass, et al., "Escape Behavior Elicited by Single, Channelrhodopsin-2-evoked Spikes in Zebrafish Somatosensory Neurons", Curr Biol., 2008, vol. 18, No. 15, pp. 1133-1137.
Ebert et al., "A Moloney MLV-rat somatotropin fusion gene produces biologically active somatotropin in a transgenic pig", Mol. Endocrinology, 1988, vol. 2, pp. 277-283.
EBI accession No. UNIPROT: A7U0Y6; "SubName: Full=Bacteriorhodopsin"; (Aug. 10, 2010).
Edelstein, et al.; "Gene therapy clinical trials worldwide 1989-2004—an overview"; The Journal of Gene Medicine; vol. 6, pp. 597-602 (2004).
Ehrlich I. et al. "Amygdala inhibitory circuits and the control of fear memory", Neuron, 2009. Friedrich Meischer Institute, vol. 62: pp. 757-771.
Eijkelkamp, et al. "Neurological perspectives on voltage-gated sodium channels", Brain (Sep. 2012), 135(Pt 9):2585-2612.
Eisen, "Treatment of amyotrophic lateral sclerosis", Drugs Aging, 1999; vol. 14, No. 3, pp. 173-96.
Emerich, et al. "A Novel Approach to Neural Transplantation in Parkinson's Disease: Use of Polymer-Encapsulated Cell Therapy", Neuroscience and Biobehavioral Reviews, 1992, vol. 16, pp. 437-447.
Ensell, et al. "Silicon-based microelectrodes for neurophysiology, micromachined from silicon-on-insulator wafers," Med. Biol. Eng. Comput., 2000, vol. 38, pp. 175-179.
Ernst, et al. "Photoactivation of Channelrhodopsin", 2008, vol. 283, No. 3, pp. 1637-1643.
Esposito et al. "The integrase family of tyrosine recombinases: evolution of a conserved active site domain" , Nucleic Acids Research, 1997, vol. 25, No. 18, pp. 3605-3614.
Evanko "Optical excitation yin and yang" Nature Methods, 2007, 4:384.
Fabian et al. "Transneuronal transport of lectins" Brain Research, 1985, vol. 344, pp. 41-48.
Falconer et al. "High-throughput screening for ion channel modulators," Journal of Biomolecular Screening, 2002, vol. 7, No. 5, pp. 460-465.
Fanselow, et al.; "Why We Think Plasticity Underlying Pavlovian Fear Conditioning Occurs in the Basolateral Amygdala"; Neuron; vol. 23, pp. 229-232 (Jun. 1999).
Farber, et al. "Identification of Presynaptic Neurons by Laser Photostimulation", Science, 1983, vol. 222, pp. 1025-1027.
Feng, et al. "Imaging Neuronal Subsets in Transgenic Mice Expressing Multiple Spectral Variants of GFP", Neuron, 2000, vol. 28, pp. 41-51.
Fenno et al., "The development and application of optogenetics", Annual Review of Neuroscience, 2011, vol. 34, No. 1, pp. 389-412.
Ferenczi, et al.; "Optogenetic approaches addressing extracellular modulation of neural excitability"; Scientific Reports; vol. 6, 20 pages (Apr. 5, 2016).
Fiala et al., "Optogenetic approaches in neuroscience", Current Biology, Oct. 2010, 20(20):R897-R903.
Fisher, J. et al. "Spatiotemporal Activity Patterns During Respiratory Rhythmogenesis in the Rat Ventrolateral Medulla," The Journal of Neurophysiol, 2006, vol. 95, pp. 1982-1991.
Fitzsimons et al., "Promotors and Regulatory Elements that Improve Adeno-Associated Virus Transgene Expression in the Brain", 2002, Methods, vol. 28, pp. 227-236.
Foster, "Bright blue times", Nature, 2005, vol. 433, pp. 698-699.
Fox et al., "A gene neuron expression fingerprint of C. elegans embryonic motor neurons", BMC Genomics, 2005, 6(42):1-23.
Friedman, et al.; "Programmed Acute Electrical Stimulation of Ventral Tegmental Area Alleviates Depressive-Like Behavior"; Neuropsychopharmacology; vol. 34, pp. 1057-1066 (2009).
Friedman, et al.; "VTA Dopamine Neuron Bursting is Altered in an Animal Model of Depression and Corrected by Desipramine"; J. Mol. Neurosci.; vol. 34, pp. 201-209 (2008).
Garrido et al., "A targeting motif involved in sodium channel clustering at the axonal initial segment", Science (Jun. 2003), 300(5628):2091-4.
Gelvich et al. "Contact flexible microstrip applicators (CFMA) in a range from microwaves up to short waves," IEEE Transactions on Biomedical Engineering, 2002, vol. 49, Issue 9: 1015-1023.
Genbank Accession No. AAG01180.1; Idnurm, et al.; pp. 1 (Mar. 21, 2001).
Genbank Accession No. ABT17417.1; Sharma, et al.; pp. 1 (Aug. 15, 2007).
GenBank Accession No. AC096118.6; Rattus norvegicus clone CH230-11 B15, 1-4, 24-25, Working Draft Sequence, 3 unordered pieces. May 10, 2003.
Genbank Accession No. BAA09452.1; Mukohata et al.; pp. 1 (Feb. 10, 1999).
Genbank Accession No. DQ094781 (Jan. 15, 2008).
GenBank Accession No. U79717.1; Rattus norvegicus dopamine 02 receptor 1-4, 24-25 gene, promoter region and exon 1. Jan. 31, 1997.
Gerits, et al.; "Optogenetically Induced Behavioral and Functional Network Changes in Primates"; Current Biology; vol. 22, pp. 1722-1726 (Sep. 25, 2012).
Gigg, et al. "Glutamatergic hippocampal formation projections to prefrontal cortex in the rat are regulated by GABAergic inhibition and show convergence with glutamatergic projections from the limbic thalamus," Hippocampus, 1994, vol. 4, No. 2, pp. 189-198.
Gilman, et al. "Isolation of sigma-28-specific promoters from Bacillus subtilis DNA" Gene, 1984, vol. 32(1-2): pp. 11-20.
Glick et al. "Factors affecting the expression of foreign proteins in Escherichia coli", Journal of Industrial Microbiology, 1987, vol. 1(5): pp. 277-282.
Goekoop, R. et al. "Cholinergic challenge in Alzheimer patients and mild cognitive impairment differentially affects hippocampal activation—a pharmacological fMRI study." Brain, 2006, vol. 129, pp. 141-157.
Gold, et al. "Representation of a perceptual decision in developing oculomotor commands", Nature, 2000, vol. 404, pp. 390-394.
Gong, et al.; "Enhanced Archaerhodopsin Fluorescent Protein Voltage Indicators"; PLOS One; vol. 8, Issue 6, 10 pages (Jun. 2013).
Gonzalez, et al., "Cell-Based Assays and Instrumentation for Screening Ion-Channel Targets", DDT, 1999, vol. 4, No. 9, pp. 431439.
Gordon, et al. "Regulation of Thy-1 Gene Expression in Transgenic Mice", Cell, 1987, vol. 50, pp. 445-452.
Gorelova et al., "The course of neural projection from the prefrontal cortex to the nucleus accumbens in the rat", Neuroscience, 1997, vol. 76, No. 3, pp. 689-706.
Goshen et al. "Dynamics of Retrieval Strategies for Remote Memories", Cell, 2011, vol. 147: pp. 678-589.
Goshen, et al.; "Dynamics of Retrieval Strategies for Remote Memories"; Cell; vol. 147, pp. 678-689 (Oct. 28, 2011).
Gottesman et al."Bacterial regulation: global regulatory networks," Ann. Rev. Genet. , 1984, vol. 18, pp. 415-441.
Gradinaru et al. (2008) Brain Cell Biology, vol. 36, 129-139. *
Gradinaru et al., "Optical deconstruction of parkinsonian neural circuitry", Science, Apr. 2009, 324(5925):354-359.
Gradinaru et al., "Targeting and readout strategies for fast optical neural control in vitro and in vivo", J Neuroscience, 2007, 27(52):14231-14238.
Gradinaru, et al. "ENpHR: a Natronomonas Halorhodopsin Enhanced for Optogenetic Applications", 2008, Brain Cell Biol., vol. 36 (1-4), pp. 129-139.
Gradinaru, et al., Molecular and Cellular Approaches for Diversifying and Extending Optogenetics, Cell, 2010, vol. 141, No. 1, pp. 154-165.
Grady, et al.; "Age-Related Reductions in Human Recognition Memory Due to Impaired Encoding"; Science; vol. 269, No. 5221, pp. 218-221 (Jul. 14, 1995).
Greenberg, et al. "Three-year outcomes in deep brain stimulation for highly resistant obsessive-compulsive disorder," Neuropsychopharmacology, 2006, vol. 31, pp. 2384-2393.
Gregory, et al. "Integration site for Streptomyces phage φBT1 and development of site-specific integrating vectors", Journal of Bacteriology, 2003, vol. 185, No. 17, pp. 5320-5323.
Gritton, et al.; "Optogenetically-evoked cortical cholinergic transients in mice expressing channelrhodopsin-2 (ChR2) in cholinergic neurons"; Society for Neuroscience Abstract Viewer and Itinery Planner & 40th Annual Meeting of the Society-for-Neuroscience; vol. 40, 2 pages (2010).
Groth et al. "Phage integrases: biology and applications," Journal of Molecular Biology, 2004, vol. 335, pp. 667-678.
Groth, et al. "A phage integrase directs efficient site-specific integration in human cells", PNAS, 2000, vol. 97, No. 11, pp. 5995-6000.
Guatteo, et al. "Temperature sensitivity of dopaminergic neurons of the substantia nigra pars compacta: Involvement of transient receptor potential channels," Journal of Neurophysiol. , 2005, vol. 94, pp. 3069-3080.
Gulick, et al. "Transfection using DEAE-Dextran" Supplement 40, Current Protocols in Molecular Biology, 1997, Supplement 40, 9.2.1-9.2.10.
Gunaydin et al., "Ultrafast optogenetic control", Nature Neuroscience, 2010, vol. 13, No. 3, pp. 387-392.
Gur et al., "A Dissociation Between Brain Activity and Perception: Chromatically Opponent Cortical Neurons Signal Chromatic Flicker that is not Perceived", Vision Research, 1997, vol. 37, No. 4, pp. 377-382.
Hackmann, et al.; "Static and time-resolved step-scan Fourier transform infrared investigations of the photoreaction of halorhodopsin from Natronobacterium pharaonis: consequences for models of the anion translocation mechanism"; Biophysical Journal; vol. 81, pp. 394-406 (Jul. 2001).
Hagglund, et al.; "Activation of groups of excitatory neurons in the mammalian spinal cord or hindbrain evokes locomotion"; Nature Neuroscience; vol. 13, No. 2, 8 pages (Feb. 2010).
Haim, et al.; "Gene Therapy to the Nervous System"; Stem Cell and Gene-Based Therapy; Section 2, pp. 133-154 (2006).
Hallet et al. "Transposition and site-specific recombination: adapting DNA cut-and-paste mechanisms to a variety of genetic rearrangements," FEMS Microbiology Reviews, 1997, vol. 21, No. 2, pp. 157-178.
Hamer, et al. "Regulation In Vivo of a cloned mammalian gene: cadmium induces the transcription of a mouse metallothionein gene in SV40 vectors," Journal of Molecular Applied Genetics, 1982, vol. 1, No. 4, pp. 273-288.
Hammack, et al.; "The response of neurons in the bed nucleus of the stria terminalis to serotonin Implications for anxiety"; Progress in Neuro-Psychopharmacology & Biological Psychiatry; vol. 33, pp. 1309-1320 (2009).
Hammer et al., "Spontaneous inflammatory disease in transgenic rats expressing HLA-B27 and Human β2m: an animal model of HLA-B27-associated human disorders", Cell, 1990, vol. 63, pp. 1099-1112.
Han, et a.; "Virogenetic and optogenetic mechanisms to define potential therapeutic targets in psychiatric disorders"; Neuropharmacology; vol. 62, pp. 89-100 (2012).
Han, et al., "Millisecond-Timescale Optical Control of Neural Dynamics in the Nonhuman Primate Brain"; Neuron; vol. 62, pp. 191-198 (Apr. 30, 2009).
Han, et al., "Multiple-Color Optical Activation, Silencing, and Desynchronization of Neural Activity with Single-Spike Temporal Resolution", PLoS One, 2007, vol. 2, No. 3, pp. 1-12.
Han, et al.; "A high-light sensitivity optical neural silencer: development and application to optogenetic control of non-human primate cortex"; Frontiers in Systems Neuroscience; vol. 5, Article 18, pp. 1-8 (Apr. 2011).
Han, et al.; "Optogenetics in the nonhuman primate"; Prog. Brain Res.; vol. 196, pp. 215-233 (2012).
Han; et al., "Two-color, bi-directional optical voltage control of genetically-targeted neurons", CoSyne (2007), Abstract Presentation, Poster III-67, p. 269, Presented Feb. 24, 2007.
Hausser, et al. "Tonic Synaptic Inhibition Modulates Neuronal Output Pattern and Spatiotemporal Synaptic Integration", Neuron, 1997, vol. 19, pp. 665-678.
Hegemann et al., "All-trans Retinal Constitutes the Functional Chromophore in Chlamydomonas rhodopsin", Biophys. J. , 1991, vol. 60, pp. 1477-1489.
Herlitze, et al., "New Optical Tools for Controlling Neuronal Activity", 2007, Curr Opin Neurobiol, vol. 17, No. 1, pp. 87-94.
Herry, et al. "Switching on and off fear by distinct neuronal circuits," Nature, 2008, vol. 454, pp. 600-606.
Heymann, et al.; "Expression of Bacteriorhodopsin in Sf9 and COS-1 Cells"; Journal of Bioenergetics and Biomembranes; vol. 29, No. 1, pp. 55-59 (1997).
Hikida et al., "Acetylcholine enhancement in the nucleus accumbens prevents addictive behaviors of cocaine and morphine", PNAS, May 2003, 100(10):6169-6173.
Hikida et al., "Increased sensitivity to cocaine by cholinergic cell ablation in nucleus accumbens", PNAS, Nov. 2001, 98(23): 13351-13354.
Hildebrandt et al, "Bacteriorhodopsin expressed in Schizosaccharomyces pombe pumps protons through the plasma membrane," PNAS, 1993, vol. 90, pp. 3578-3582.
Hira et al., "Transcranial optogenetic stimulation for functional mapping of the motor cortex", J Neurosci Methods, 2009, vol. 179, pp. 258-263.
Hirase, et al. "Multiphoton stimulation of neurons", J Neurobiol, 2002, vol. 51, No. 3: pp. 237-247.
Hodaie, et al., "Chronic Anterior Thalamus Stimulation for Intractable Epilepsy," Epilepsia, 2002, vol. 43, pp. 603-608.
Hoffman et al., "K+ Channel Regulation of Signal Propagation in Dendrites of Hippocampal Pyramidal Neurons", 1997, Nature, vol. 387: pp. 869-874.
Hofherr et al. (2005) Journal of Cell Science, vol. 118, 1935-1943. *
Hofherr et al. "Selective Golgi export of Kir2.1 controls the stoichiometry of functional Kr2.x channel heteromers" Journal of Cell Science, 2005, vol. 118, p. 1935-1943.
Hosokawa, T. et al. "Imaging spatio-temporal patterns of long-term potentiation in mouse hippocampus." Philos. Trans. R. Soc. Lond. B., 2003, vol. 358, pp. 689-693.
Hososhima, et al.; "Near-infrared (NIR) up-conversion optogenetics"; Optical Techniques in Neurosurgery, Neurophotonics, and Optogenetics II; vol. 9305, doi: 10.1117/12.2078875, 4 pages. (2015).
Hustler; et al., "Acetylcholinesterase staining in human auditory and language cortices: regional variation of structural features", Cereb Cortex (Mar.-Apr. 1996), 6(2):260-70.
Hynynen, et al. "Clinical applications of focused ultrasound—The brain." Int. J. Hyperthermia, 2007, vol. 23, No. 2: pp. 193-202.
Ibbin I, et al.; "A Field Conjugation Method for Direct Synthesis of Hyperthermia Phased-Array Heating Patterns"; IEEE Transactions on Ultrasonics, Ferroelectrics, and Frequency Control; vol. 36, No. 1, pp. 3-9 (Jan. 1989).
Ihara, et al.; "Evolution of the Archaeal Rhodopsins: Evolution Rate Changes by Gene Duplication and Functional Differentiation"; J. Mol. Biol.; vol. 285, pp. 163-174 (1999).
International Search Report for International Application No. PCT/US2009/053474, dated Oct. 8, 2009.
Isenberg et al. "Cloning of a Putative Neuronal Nicotinic Aceylcholine Receptor Subunit," Journal of Neurochemistry, 1989, pp. 988-991.
Iyer et al., "Virally mediated optogenetic excitation and inhibition of pain in freely moving nontransgenic mice", Nat Biotechnol., (Mar. 2014), 32(3):274-8.
Jekely, "Evolution of Phototaxis", 2009, Phil. Trans. R. Soc. B, vol. 364, pp. 2795-2808.
Jennings et al., "Distinct extended amygdala circuits for divergent motivational states," Nature (Apr. 2013), 496 (7444):224-8.
Ji et al., "Light-evoked Somatosensory Perception of Transgenic Rats that Express Channelrhodopsin-2 in Dorsal Root Ganglion Cells", PLoS One (2012), 7(3):e32699.
Jimenez S.A & Maren S. et al/ "Nuclear disconnection within the amygdala reveals a direct pathway to fear", Learning Memory, 2009, vol. 16: pp. 766-768.
Johansen, et al., "Optical Activation of Lateral Amygdala Pyramidal Cells Instructs Associative Fear Learning", 2010, PNAS, vol. 107, No. 28, pp. 12692-12697.
Johansen, et al.; "Controlling the elements: an optogenetic approach to understanding the neural circuits of fear"; Biol. Psychiatry; vol. 71, No. 12, pp. 1053-1060 (Jun. 15, 2012).
Johnson, et al.; "Differential Biodistribution of Adenoviral Vector In Vivo as Monitored by Bioluminescence Imaging and Quantitative Polymerase Chain Reaction"; Human Gene Therapy; vol. 17, pp. 1262-1269 (Dec. 2006).
Johnson-Saliba, et al.; "Gene Therapy: Optimising DNA Delivery to the Nucleus"; Current Drug Targets; vol. 2, pp. 371-399 (2001).
Johnston et al. "Isolation of the yeast regulatory gene GAL4 and analysis of its dosage effects on the galactose/melibiose regulon," PNAS, 1982, vol. 79, pp. 6971-6975.
Jones, et al.; "Animal Models of Schizophrenia"; British Journal of Pharmacology; vol. 164, pp. 1162-1194 (2011).
Kaiser; "Clinical research. Death prompts a review of gene therapy vector"; Science; 317(5838):580 (Aug. 3, 2007).
Kandel, E.R., et al. "Electrophysiology of Hippocampal Neurons: I. Sequential Invasion and Synaptic Organization," J Neurophysiol, 1961, vol. 24, pp. 225-242.
Kandel, E.R., et al. "Electrophysiology of Hippocampal Neurons: II. After- Potentials and Repetitive Firing", J Neurophysiol., 1961, vol. 24, pp. 243-259.
Karra, et al. "Transfection Techniques for Neuronal Cells", The Journal of Neuroscience, 2010, vol. 30, No. 18, pp. 6171-6177.
Karreman et al. "On the use of double FLP recognition targets (FRTs) in the LTR of retroviruses for the construction of high producer cell lines" , Nucleic Acids Research, 1996, vol. 24, No. 9: pp. 1616-1624.
Kato et al. "Present and future status of noninvasive selective deep heating using RF in hyperthermia." Med & Biol. Eng. & Comput 31 Supp: S2-11, 1993. Abstract. p. S2 only.
Katz, et al. "Scanning laser photostimulation: a new approach for analyzing brain circuits," Journal of Neuroscience Methods, 1994, vol. 54, pp. 205-218.
Kay; "State-of-the-art gene-based therapies: the road ahead"; Nature Reviews Genetics; vol. 12, pp. 316-328 (May 2011).
Kelder et al., "Glycoconjugates in human and transgenic animal milk", Advances in Exp. Med. and Biol., 2001, vol. 501, pp. 269-278.
Kessler, et al.; "Gene delivery to skeletal muscle results in sustained expression and systemic delivery of a therapeutic protein"; Proc. Natl. Acad. Sci. USA; vol. 93, pp. 14082-14087 (Nov. 1996).
Khodakaramian, et al. "Expression of Cre Recombinase during Transient Phage Infection Permits Efficient Marker Removal in Streptomyces," Nucleic Acids Research, 2006, vol. 34, No. 3:e20, pp. 1-5.
Khosravani et al., "Voltage-Gated Calcium Channels and Idiopathic Generalized Epilepsies", Physiol. Rev., 2006, vol. 86: pp. 941-966.
Kianianmomeni, et al. "Channelrhodopsins of Volvox carteri are Photochromic Proteins that are Specifically Expressed in Somatic Cells under Control of Light, Temperature, and the Sex Inducer", 2009, Plant Physiology, vol. 151, No. 1, pp. 347-366.
Kim et al., "Diverging neural pathways assemble a behavioural state from separable features in anxiety" Nature (Apr. 2013), 496(7444):219-23.
Kim et al., "Light-Driven Activation of β2-Adrenergic Receptor Signaling by a Chimeric Rhodopsin Containing the β2-Adrenergic Receptor Cytoplasmic Loops," Biochemistry, 2005, vol. 44, No. 7, pp. 2284-2292.
Kim et al., "PDZ domain proteins of synapses", Nature Reviews Neuroscience, (Oct. 2004), 5(10):771-81.
Kingston et al. "Transfection and Expression of Cloned DNA," Supplement 31, Current Protocols in Immunology, 1999, 10.13.1-10.13.9.
Kingston et al. "Transfection of DNA into Eukaryotic Cells," Supplement 63, Current Protocols in Molecular Biology, 1996, 9.1.1-9.1.11, 11 pages.
Kinoshita, et al., "Optogenetically Induced Supression of Neural Activity in the Macaque Motor Cortex", Poster Sessions Somatomotor System, Others,2010, pp. 141-154.
Kita, H. et al. "Effects of dopamine agonists and antagonists on optical responses evoked in rat frontal cortex slices after stimulation of the subcortical white matter," Exp. Brain Research, 1999, vol. 125, pp. 383-388.
Kitabatake et al., "Impairment of reward-related learning by cholinergic cell ablation in the striatum", PNAS, Jun. 2003, 100(13):7965-7970.
Kitayama, et al. "Regulation of neuronal differentiation by N-methyl-D-aspartate receptors expressed in neural progenitor cells isolated from adult mouse hippocampus," Journal of Neurosci Research, 2004, vol. 76, No. 5: pp. 599-612.
Klausberger, et al. "Brain-state- and cell-type-specific firing of hippocampal interneurons in vivo", Nature, 2003, vol. 421: pp. 844-848.
Kleinlogel, et al.; "A gene-fusion strategy for stoichiometric and co-localized expression of light-gated membrane proteins"; Nature Methods; vol. 8, No. 12, pp. 1083-1091 (Dec. 2011).
Knopfel, et al. "Optical Probin of Neuronal Circuit Dynamics: Gentically Encoded Versus Classical Fluorescent Sensors", 2006, Trends Neurosci, vol. 29, No. 3, pp. 160-166.
Knopfel, et al.; "A comprehensive concept of optogenetics"; Progress in Brain Research; vol. 196, pp. 1-28 (2012).
Knopfel, et al.; "Remote control of cells"; Nature Nanotechnology; vol. 5, pp. 560-561 (Aug. 2010).
Knox, et al.; "Heterologous Expression of Limulus Rhodopsin"; The Journal of Biological Chemistry; vol. 278, No. 42, pp. 40493-40502 (Oct. 17, 2003).
Kocsis et al., "Regenerating Mammalian Nerve Fibres: Changes in Action Potential Wavefrom and Firing Characteristics Following Blockage of Potassium Conductance", 1982, Proc. R. Soc. Lond., vol. B 217: pp. 77-87.
Kokel et al., "Photochemical activation of TRPA1 channels in neurons and animals", Nat Chem Biol (Apr. 2013), 9(4):257-63.
Kravitz, et al.; "Regulation of parkinsonian motor behaviours by optogenetic control of basal ganglia circuitry"; Nature; vol. 466, No. 622, 8 pages (Jul. 29, 2010).
Kugler, et al.; "Neuron-Specific Expression of Therapeutic Proteins: Evaluation of Different Cellular Promoters in Recombinant Adenoviral Vectors"; Molecular and Cellular Neuroscience; vol. 17, pp. 78-96 (2001).
Kuhlman et al. (2008) "High-Resolution Labeling and Functional Manipulation of Specific Neuron Types in Mouse Brain by Cre-Activated Viral Gene Expression" PLoS One, 2005, vol. 3, No. 4, pp. 1-11.
Kunkler, P. et at. "Optical Current Source Density Analysis in Hippocampal Organotypic Culture Shows that Spreading Depression Occurs with Uniquely Reversing Current," The Journal of Neuroscience, 2005, vol. 25, No. 15, pp. 3952-3961.
Lalumiere, R., "A new technique for controlling the brain: optogenetics and its potential for use in research and the clinic", Brain Stimulation, 2011, vol. 4, pp. 1-6.
Lammel et al., "Input-specific control of reward and aversion in the ventral tegmental area", Nature (Nov. 2012), 491 (7423): 212-7.
Landy, A. "Mechanistic and structural complexity in the site-specific recombination pathways of Int and FLP", Current Opinion in Genetics and Development, 1993, vol. 3, pp. 699-707.
Lanyi et al. (1990) J. Biol. Chem., vol. 265(3), 1253-1260. *
Lanyi et al. "The primary structure of a Halorhodopsin from Natronobacterium Pharaonis" Journal of Biological Chemistry 1990, vol. 265, No. 3, p. 1253-1260.
Lee et al. "Sterotactic Injection of Adenoviral Vectors that Target Gene Expression to Specific Pituitary Cell Types: Implications for Gene Therapy", Neurosurgery, 2000, vol. 46, No. 6: pp. 1461-1469.
Lee et al., "Potassium Channel Gone Therapy Can Prevent Neuron Deatch Resulting from Necrotic and Apoptotic Insults", Journal of Neurochemistry, 2003, vol. 85: pp. 1079-1088.
Levitan et al. "Surface Expression of Kv1 Voltage-Gated K+ Channels Is Governed by a C-terminal Motif," Trends Cardiovasc. Med., 2000, vol. 10, No. 7, pp. 317-320.
Li et al. "Fast noninvasive activation and inhibition of neural and network activity by vertebrate rhodopsin and green algae channelrhodopsin." PNAS, 2005, vol. 102, No. 49, p. 17816-17821.
Li et al., "Surface Expression of Kv1 Channels is Governed by a C-Terminal Motif", J. Bioi. Chem. (2000), 275(16):11597-11602.
Li, et al.; "A Method for Activiation of Endogenous Acid-sensing Ion Channel 1 a (ASIC1a) in the Nervous System with High Spatial and Temporal Precision"; The Journal of Biological Chemistry; vol. 289, No. 22, pp. 15441-15448 (May 30, 2014).
Lim et al., "A Novel Targeting Signal for Proximal Clustering of the Kv2.1K+ Channel in Hippocampal Neurons", Neuron, 2000, vol. 25: pp. 385-397.
Lima, et al. "Remote Control of Behavior through Genetically Targeted Photostimulation of Neurons", Cell, 2005, vol. 121: pp. 141-152.
Liman, et al. "Subunit Stoichiometry of a Mammalian K+ Channel Determined by Construction of Multimeric cDNAs," Neuron, 1992, vol. 9, pp. 861-871.
Lin, "A users guide to channelrhodopsin variants: features, limitations and future developments", Exp Physiol, 2010, vol. 96, No. 1, pp. 19-25.
Lin, et al.; "Characterization of Engineered Channelrhodopsin Variants with Improved Properties and Kinetics"; Biophysical Journal; vol. 96, No. 5, pp. 1803-1814 (Mar. 2009).
Lin, et al.; "Study of the Circuitry of Nucleus Accumbens and its Effect on Addiction by Optogenetic Methods: 964"; Neurosurgery; vol. 67, No. 2, pp. 557 (Aug. 2010).
Liske et al., "Optical inhibition of motor nerve and muscle activity in vivo", Muscle Nerve (Jun. 2013), 47(6):916-21.
Liu et al., "Optogenetics 3.0", Cell, Apr. 2010, 141(1):22-24.
Llewellyn et al., "Orderly recruitment of motor units under optical control in vivo", Nature Medicine, (Oct. 2010), 16 (10):1161-5.
Loetterle, et al., "Cerebellar Stimulation: Pacing the Brain", American Journal of Nursing, 1975, vol. 75, No. 6, pp. 958-960.
Lonnerberg et al. "Regulatory Region in Choline Acetyltransferase Gene Directs Developmental and Tissue-Specific Expression in Transgenic mice", Proc. Natl. Acad. Sci. USA (1995), 92(9):4046-4050.
Louis et al. "Cloning and sequencing of the cellular-viral junctions from the human adenovirus type 5 transformed 293 cell line," Virology, 1997, vol. 233, pp. 423-429.
Luecke, et al. "Structural Changes in Bacteriorhodopsin During Ion Transport at 2 Angstrom Resolution," Science, 1999, vol. 286, pp. 255-260.
Luo, et al.; "Synthetic DNA delivery systems"; Nature Biotechnology; vol. 18, pp. 33-37 (Jan. 2000).
Lyznik, et al. "FLP-mediated recombination of FRT sites in the maize genome," Nucleic Acids Research, 1996, vol. 24, No. 19: pp. 3784-3789.
Ma et al. "Role of ER Export Signals in Controlling Surface Potassium Channel Numbers," Science, 2001, vol. 291, pp. 316-319.
Maestripieri, et al.; "A modest proposal: displacement activities as an indicator of emotions in primates"; Anim. Behav.; vol. 44, pp. 967-979 (1992).
Malin et al., "Involvement of the rostral anterior cingulate cortex in consolidation of inhibitory avoidance memory: Interaction with the basolateral amygdala", Neurobiol Learning Mem, 2007, 87(2):295-302.
Mancuso et al., "Optogenetic probing of functional brain circuitry", Experimental Physiology, 2010, vol. 96.1, pp. 26-33.
Mann et at. "Perisomatic Feedback Inhibition Underlies Cholinergically Induced Fast Network Oscillations in the Rat Hippocampus in Vitro," Neuron, 2005, vol. 45, 2005, pp. 105-117.
Marin, et al., The Amino Terminus of the Fourth Cytoplasmic Loop of Rhodopsin Modulates Rhodopsin-Transduction Interaction, The Journal of Biological Chemistry, 2000, vol. 275, pp. 1930-1936.
Masaki, et al.; "(β-Adrenergic Receptor Regulation of the Cardiac L-Type Ca2+ Channel Coexpressed in a Fibroblast Cell Line"; Receptor; vol. 5, pp. 219-231 (1996).
Mattis et al., "Principles for applying optogenetic tools derived from direct comparative analysis of microbial opsins", Nat Methods (Dec. 2011), 9(2):159-72.
Mattson, "Apoptosis in Neurodegenerative Disorders", Nature Reviews, 2000, vol. 1: pp. 120-129.
Mayberg et al. "Deep Brain Stimulation for Treatment-Resistant Depression," Focus, 2008, vol. VI, No. 1, pp. 143-154.
Mayford et al., "Control of memory formation through regulated expression of CAMKII Transgene", Science, Dec. 1996, 274:1678-1683.
McAllister, "Cellular and Molecular Mechanisms of Dendrite Growth", 2000, Cereb Cortex, vol. 10, No. 10, pp. 963-973.
McKenzie, et al.; "New approach illuminates how memory systems switch"; Trends in Cognitive Sciences; vol. 16, No. 2 (Feb. 2012).
McKnight "Functional relationships between transcriptional control signals of the thymidine kinase gene of herpes simplex virus", Cell, 1982, vol. 31 pp. 355-365.
Melyan, Z., et al. "Addition of human melanopsin renders mammalian cells Photoresponsive", Nature, 2005, vol. 433: pp. 741-745.
Mermelstein, et al. "Critical Dependence of cAMP Response Element-Binding Protein Phosphorylation on L-Type Calcium Channels Supports a Selective Response to EPSPs in Preference to Action Potentials", The Journal of Neuroscience, 2000, vol. 20, No. 1, pp. 266-273.
Meyer, et al. "High density interconnects and flexible hybrid assemblies for active biomedical implants," IEEE Transactions on Advanced Packaging, 2001, vol. 24, No. 3, pp. 366-372.
Milella et al. "Opposite roles of dopamine and orexin in quinpirole-induced excessive drinking: a rat model of psychotic polydipsia" Psychopharmacology, 2010, 211:355-366.
Monje et al., "Irradiation Induces Neural Precursor-Cell Dysfunction", Natural Medicine, 2002, vol. 8, No. 9, pp. 955-962.
Morelli et al., "Neuronal and glial cell type-specific promoters within adenovirus recombinants restrict the expression of the apoptosis-inducing molecule Fas ligand to predetermined brain cell types, and abolish peripheral liver toxicity", Journal of General Virology, 1999, 80:571-583.
Mortensen et al. "Selection of Transfected Mammalian Cells," Supplement 86, Current Protocols in Molecular Biology, 1997, 9.5.1-09.5.19.
Mourot et al., "Rapid Optical Control of Nociception with an Ion Channel Photoswitch", Nat Methods (Feb. 2012), 9 (4):396-402.
Mueller, et al.; "Clinical Gene Therapy Using Recombinant Adeno-Associated Virus Vectors"; Gene Therapy; vol. 15, pp. 858-863 (2008).
Mullins et al., "Expression of the DBA/2J Ren-2 gene in the adrenal gland of transgenic mice", EMBO, 1989, vol. 8, pp. 4065-4072.
Mullins et al., "Fulminant hypertension in transgenic rats harbouring the mouse Ren-2 gene", Nature, 1990, vol. 344, pp. 541-544.
Nacher, et al. "NMDA receptor antagonist treatment increases the production of newneurons in the aged rat hippocampus", Neurobiology of Aging, 2003,vol. 24, No. 2: pp. 273-284.
Nagel et al. "Functional Expression of Bacteriorhodopsin in Oocytes Allows Direct Measurement of Voltage Dependence of Light Induced H+ Pumping," FEBS Letters, 1995, vol. 377, pp. 263-266.
Nagel, et al. "Channelrhodopsin-2, a directly light-gated cation-selective membrane channel", PNAS, 2003, vol. 100, No. 24: pp. 13940-13945.
Nagel, et al. "Channelrhodopsin-I: a light-gated proton channel in green algae", Science, 2002, vol. 296: pp. 2395-2398.
Nakagami, et al. "Optical Recording of Trisynaptic Pathway in Rat Hippocampal Slices with a Voltage-Sensitive Dye" Neuroscience, 1997, vol. 81, No. 1, pp. 1-8.
Naqvi, et al. "Damage to the insula disrupts addiction to cigarette smoking," Science; 2007, vol. 315 pp. 531-534.
Natochin, et al. "Probing rhodopsin-transducin interaction using Drosophila Rh1-bovine rhodopsin chimeras," Vision Res., 2006, vol. 46, No. 27: pp. 4575-4581.
Nelson, et al.; "Non-Human Primates: Model Animals for Developmental Psychopathology"; Neuropsychopharmacology; vol. 34, No. 1, pp. 90-105 (Jan. 2009).
Nieh et al., "Optogenetic dissection of neural circuits underlying emotional valence and motivated behaviors", Brain Research, (May 2012), 1511:73-92.
Nirenberg, et al. "The Light Response of Retinal Ganglion Cells is Truncated by a Displaced Amacrine Circuit", Neuron, 1997, vol. 18: pp. 637-650.
Nonet, "Visualization of synaptic specializations in live C. elegans with synaptic vesicle protein-GFP fusions", J. Neurosci. Methods, 1999, 89:33-40.
Nunes-Duby, et al. "Similarities and differences among 105 members of the Int family of site-specific recombinases", Nucleic Acids Research, 1998, vol. 26, No. 2: pp. 391-406.
O'Gorman et al. "Recombinase-mediated gene activation and site-specific integration in mammalian cells", Science, 1991, 251(4999): pp. 1351-1355.
Olivares (2001) "Phage R4 integrase mediates site-specific integration in human cells", Gene, 2001, vol. 278, pp. 167-176.
Ory, et al. "A stable human-derived packaging cell line for production of high titer retrovirus/vesicular stomatitis virus G pseudotypes," PNAS, 1996, vol. 93: pp. 11400-11406.
Packer, et al.; "Targeting Neurons and Photons for Optogenetics"; Nature Neuroscience; vol. 16, No. 7, pp. 805-815 (Jul. 2013).
Palmer et al., "Fibroblast Growth Factor-2 Activates a Latent Neurogenic Program in Neural Stem Cells from Diverse Regions of the Adult CNS", The Journal of Neuroscience, 1999, vol. 19, pp. 8487-8497.
Palmer et al., "The Adult Rat Hippocampus Contains Primordial Neural Stem Cells", Molecular and Cellular Neuroscience, 1997, vol. 8, pp. 389-404.
Palu, et al.; "In pursuit of new developments for gene therapy of human diseases"; Journal of Biotechnology; vol. 68, pp. 1-13 (1999).
Pan et al. "Functional Expression of a Directly Light-Gated Membrane Channel in Mammalian Retinal Neurons: A Potential Strategy for Restoring Light Sensitivity to the Retina After Photoreceptor Degeneration," Investigative Opthalmology & Visual Science, 2005, 46 E-Abstract 4631. Abstract only.
Panda, et al. "Illumination of the Melanopsin Signaling Pathway", Science, 2005, vol. 305: pp. 600-604.
Pandya, et al.; "Where in the Brain Is Depression?"; Curr. Psychiatry Rep.; vol. 14, pp. 634-642 (2012).
Pape, et al., "Plastic Synaptic Networks of the Amygdala for the Acquisition, Expression, and Extinction of Conditioned Fear", 2010, Physiol Rev, vol. 90, pp. 419-463.
Paulhe et al. "Specific Endoplasmic Reticulum Export Signal Drives Transport of Stem Cell Factor (Kitl) to the Cell Surface," The Journal of Biological Chemistry, 2004, vol. 279, No. 53, p. 55545-55555.
Pear "Transient Transfection Methods for Preparation of High-Titer Retroviral Supernatants" Supplement 68, Current Protocols in Molecular Biology, 1996, 9.1 1 .I-9.1 1 .I 8.
Peralvarez-Marin et al., "Inter-helical hydrogen bonds are essential elements for intra-protein signal transduction: The role of Asp115 in bacteriorhodopsin transport function", J. Mol. Biol., 2007, vol. 368, pp. 666-676.
Peterlin, et al. "Optical probing of neuronal circuits with calcium indicators," PNAS, 2000, vol. 97, No. 7: pp. 3619-3624.
Petersen et al. "Spatiotemporal Dynamics of Sensory Responses in Layer 2/3 of Rat Barrel Cortex Measured In Vivo by Voltage-Sensitive Dye Imaging Combined with Whole-Cell Voltage Recordings and Neuron Reconstructions," The Journal of Neuroscience, 2003, vol. 23, No. 3, pp. 1298-1309.
Petersen, et al.; "Functionally Independent Columns of Rat Somatosensory Barrel Cortex Revealed with Voltage-Sensitive Dye Imaging"; J. of Neuroscience; vol. 21, No. 21, pp. 8435-8446 (Nov. 1, 2011).
Petrecca, et al. "Localization and Enhanced Current Density of the Kv4.2 Potassium Channel by Interaction with the Actin-Binding Protein Filamin," The Journal of Neuroscience, 2000, vol. 20, No. 23, pp. 8736-8744.
Pettit, et al. "Local Excitatory Circuits in the Intermediate Gray Layer of the Superior Colliculus", J Neurophysiol., 1999, vol. 81, No. 3: pp. 1424-1427.
Pfeifer, et al.; "Gene Therapy: Promises and Problems"; Annu. Rev. Genomics Hum. Genet.; vol. 2, pp. 177-211 (2001).
Pinkham et al., "Neural bases for impaired social cognition in schizophrenia and autism spectrum disorders", Schizophrenia Research, 2008, vol. 99, pp. 164-175.
Potter, "Transfection by Electroporation." Supplement 62, Current Protocols in Molecular Biology, 1996, 9.3.1-9.3.6.
Pouille, et al. "Routing of spike series by dynamic circuits in the hippocampus", Nature, 2004, vol. 429: pp. 717-723.
Powell, et al.; "Schizophrenia-Relevant Behavioral Testing in Rodent Models: A Uniquely Human Disorder?"; Biol. Psychiatry; vol. 59, pp. 1198-1207 (2006).
Qiu et al. "Induction of photosensitivity by heterologous expression of melanopsin", Nature, 2005, vol. 433: pp. 745-749.
Racaniello; "How many viruses on Earth?"; Virology Blog; 6 pages; http://www.virology.ws/2013/09/06/how-many-viruses-on-earth/ (Sep. 6, 2013).
Ramalho, et al.; "Mouse genetic corneal disease resulting from transgenic insertional mutagenesis"; Br. J. Ophthalmol.; vol. 88, No. 3, pp. 428-432 (Mar. 2004).
Rammes, et al., "Synaptic Plasticity in the Basolateral Amygdala in Transgenic Mice Expressing Dominant-Negative cAMP Response Element-binding Protein (CREB) in Forebrain", Eur J. Neurosci, 2000, vol. 12, No. 7, pp. 2534-2546.
Randic, et al. "Long-term Potentiation and Long-term Depression of Primary Afferent Neurotransmission in the Rat Spinal Cord", 1993, Journal of Neuroscience, vol. 13, No. 12, pp. 5228-5241.
Raper, et al.; "Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer." Mol. Genet. Metab.; vol. 80, No. 1-2, pp. 148-158 (Sep.-Oct. 2003).
Rathnasingham et al., "Characterization of implantable microfabricated fluid delivery devices," IEEE Transactions on Biomedical Engineering, 2004, vol. 51, No. 1: pp. 138-145.
RecName: Full=Halorhodopsin; Short=HR; Alt Name: Full=NpHR; XP002704922, retrieved from EBI accession No. UNIPROT: P15647. Database accession No. P15647. Apr. 1, 1990.
Rein, et al., "The Optogenetic (r)evolution", Mol. Genet. Genomics, 2012, vol. 287, No. 2, pp. 95-109.
Remy, et al., "Depression in Parkinson's Disease: Loss of Dopamine and Noradrenaline Innervation in the Limbic System", Brain, 2005, vol. 128 (Pt 6), pp. 1314-1322.
Ristevski; "Making Better Transgenic Models: Conditional, Temporal, and Spatial Approaches"; Molecular Biotechnology; vol. 29, No. 2, pp. 153-163 (Feb. 2005).
Ritter, et al., "Monitoring Light-induced Structural Changes of Channelrhodopsin-2 by UV-Visible and Fourier Transform Infared Spectroscopy", 2008, The Journal of Biological Chemistry, vol. 283, No. 50, pp. 35033-35041.
Rivera et al., "BDNF-Induced TrkB Activation Down-Regulates the K+-Cl-cotransporter KCC2 and Impairs Neuronal Cl-Extrusion", The Journal of Cell Biology, 2002, vol. 159: pp. 747-752.
Rogers, et al.; "Effects of ventral and dorsal CA1 subregional lesions on trace fear conditioning"; Neurobiology of Learning and Memory; vol. 86, pp. 72-81 (2006).
Rosenkranz, et al. "The prefrontal cortex regulates lateral amygdala neuronal plasticity and responses to previously conditioned stimuli", J. Neurosci., 2003, vol. 23, No. 35: pp. 11054-11064.
Rousche, et al., "Flexible polyimide-based intracortical electrode arrays with bioactive capability," IEEE Transactions on Biomedical Engineering, 2001, vol. 48, No. 3, pp. 361-371.
Rubinson et at. "A lentivirus-based system to functionally silence genes in primary mammalian cells, stem cells and transgenic mice by RNA interference," Nature Genetics, 2003, vol. 33, p. 401-406.
Rudiger et at. "Specific arginine and threonine residues control anion binding and transport in the light-driven chloride pump halorhodopsin," The EMBO Journal, 1997, vol. 16, No. 13, pp. 3813-3821.
Sajdyk, et al., "Excitatory Amino Acid Receptors in the Basolateral Amygdala Regulate Anxiety Responses in the Social Interaction Test", Brain Research, 1997, vol. 764, pp. 262-264.
Sakaguchi, et al.; "Inhibiting the Activity of CA1 Hippocampal Neurons Prevents the Recall of Contextual Fear Memory in Inducible ArchT Transgenic Mice"; PLoSOne; 11 pages (Jun. 15, 2015).
Salzman, et al. "Cortical microstimulation influences perceptual judgements of motion direction", Nature, 1990, vol. 346, pp. 174-177.
Samuelson, (20110 Dialogues Clin. Neurosci., vol. 13, 346-351. *
Samuelson; "Post-traumatic stress disorder and declarative memory functioning: a review"; Dialogues in Clinical Neuroscience; vol. 13, No. 3, pp. 346-351 (2011).
Santana et al., "Can Zebrafish Be Used as Animal Model to Study Alzheimer's Disease?" Am. J. Neurodegener. Dis. (2012), 1(1):32-48.
Sato et al. "Role of Anion-binding Sites in cytoplasmic and extracellular channels of Natronomonas pharaonis halorhodopsin," Biochemistry, 2005. vol. 44, pp. 4775-4784.
Sauer "Site-specific recombination: developments and applications," Current Opinion in Biotechnology, 1994, vol. 5, No. 5: pp. 521-527.
Schester, et al.; "Biodistribution of adeno-associated virus serotype 9 (AAV9) vector after intrathecal and intravenous delivery in mouse"; Frontiers in Neuroanatomy; vol. 8, Article 42, pp. 1-41 (Jun. 10, 2014).
Schiff, et al. "Behavioral improvements with thalamic stimulation after severe traumatic brain injury," Nature, 2007, vol. 448, pp. 600-604.
Schlaepfer et al. "Deep Brain stimulation to Reward Circuitry Alleviates Anhedonia in Refractory Major Depresion," Neuropsychopharmacology, 2008, vol. 33, pp. 368-377.
Schroll et al., "Light-induced activation of distinct modulatory neurons triggers appetitive or aversive learning in drosophila larvae", Current Biology, Sep. 2006, 16(17):1741-1747.
Sclimenti, et al. "Directed evolution of a recombinase for improved genomic integration at a native human sequence," Nucleic Acids Research, 2001, vol. 29, No. 24: pp. 5044-5051.
Sheikh et al., "Neurodegenerative Diseases: Multifactorial Conformational Diseases and Their Therapeutic Interventions", Journal of Neurodegenerative Diseases (2013), Article ID 563481:1-8.
Shepherd, et al. "Circuit Analysis of Experience-Dependent Plasticity in the Developing Rat Barrel Cortex", Neuron, 2003, vol. 38: pp. 277-289.
Shibasaki et al. "Effects of body temperature on neural activity in the hippocampus: Regulation of resting membrane potentials by transient receptor potential vanilloid 4," The Journal of Neuroscience, 2007, vol. 27, No. 7: pp. 1566-1575.
Shibasaki et al., "Effects of body temperature on neural activity in the hippocampus: Regulation of resting membrane potentials by transient receptor potential vanilloid 4," The Journal of Neuroscience, 2007, 27(7):1566-1575.
Shimizu, et al.; "NMDA Receptor-Dependent Synaptic Reinforcement as a Crucial Process for Memory Consolidation"; Science; vol. 290, pp. 1170-1174 (Nov. 10, 2000).
Shoji, et al.; "Current Status of Delivery Systems to Improve Target Efficacy of Oligonucleotides"; Current Pharmaceutical Design; vol. 10, pp. 785-796 (2004).
Sigmund; "Viewpoint: Are Studies in Genetically Altered Mice Out of Control?"; Arterioscler Thromb Vasc. Biol.; vol. 20, No, 6, pp. 1425-1429 (Jun. 2000).
Silver, et al. "Amino terminus of the yeast GAL4 gene product is sufficient for nuclear localization" PNAS, 1984, vol. 81, No. 19: pp. 5951-5955.
Simmons et al. "Localization and function of NK3 subtype Tachykinin receptors of layer pyramidal neurons of the guinea-pig medial prefrontal cortex", Neuroscience, 2008, vol. 156, No. 4: pp. 987-994.
Sineshchekov et al.; "Intramolecular Proton Transfer in Channelrhodopsins"; Biophysical Journal; vol. 104, No. 4, pp. 807-807 (Feb. 2013).
Sineshchekov, et al., "Two Rhodopsins Mediate Phototaxis to Low and High Intensity Light in Chlamydomas Reinhardtil", PNAS, 2002, vol. 99, No. 13, pp. 8689-8694.
Singer et al. "Elevated Intrasynaptic Dopamine Release in Tourette's Syndrome Measured by PET," American Journal of Psychiatry, 2002, vol. 159: pp. 1329-1336.
Singer; "Light Switch for Bladder Control"; Technology Review; pp. 1-2 (Sep. 14, 2009).
Skolnick, et al.; "From genes to protein structure and function: novel applications of computational approaches in the genomic era"; Trends Biotechnol; vol. 18, No. 1, pp. 34-39 (Jan. 2000).
Slamovits et al., "A bacterial proteorhodopsin proton pump in marie eukaryotes", Nature Communications (Feb. 2011), 2:183.
Slimko et al., "Selective Electrical Silencing of Mammalian Neurons In Vitro by the use of Invertebrate Ligand-Gated Chloride Channels", The Journal of Neuroscience, 2002, vol. 22, No. 17: pp. 7373-7379.
Smith et al. "Diversity in the serine recombinases", Molecular Microbiology, 2002, vol. 44, No. 2: pp. 299-307.
Smith, et al.; "Proton binding sites involved in the activation of acid-sensing ion channel ASIC2a"; Neuroscience Letters; vol. 426, pp. 12-17 (2007).
Sofuoglu, et al.; "Cholinergic Functioning in Stimulant Addiction: Implications for Medications Development"; CNS Drugs; vol. 23, No. 11, pp. 939-952 (Nov. 1, 2009).
Sohal et al., "Parvalbumin neurons and gamma rhythms enhance cortical circuit performance", Nature, 2009, vol. 459, No. 7247, pp. 698-702.
Song et al. "Differential Effect of TEA on Long-Term Synaptic Modification in Hippocampal CA1 and Dentate Gyrus in vitro." Neurobiology of Learning and Memory, 2001, vol. 76, No. 3, pp. 375-387.
Song, "Genes responsible for native depolarization-activated K+ currents in neurons," Neuroscience Research, 2002, vol. 42, pp. 7-14.
Soofiyani, et al.; "Gene Therapy, Early Promises, Subsequent Problems, and Recent Breakthroughs"; Advanced Pharmaceutical Bulletin; vol. 3, No. 2, pp. 249-255 (2013).
Stark, et al. "Catalysis by site-specific recombinases," Trends Genet., 1992, vol. 8, No. 12: pp. 432-439.
Steimer; "The biology of fear- and anxiety-related behaviors"; Dialogues in Clinical Neuroscience; vol. 4, No. 3, pp. 231-249 (Sep. 2002).
Stockklausner et al. "A sequence motif responsible for ER export and surface expression of Kir2.0 inward rectifier K+ channels," FEBS Letters, 2001, vol. 493, pp. 129-133.
Stoll, et al. "Phage TP901-I site-specific integrase functions in human cells," Journal of Bacteriology, 2002, vol. 184, No. 13: pp. 3657-3663.
Stonehouse, et al.; "Caffeine Regulates Neuronal Expression of the Dopamine 2 Receptor Gene"; Molecular Pharmacology; vol. 64, No. 6, pp. 1463-1473 (2003).
Stuber; "Dissecting the neural circuitry of addiction and psychiatric disease with optogenetics"; Neuropsychopharmacology; vol. 35, No. 1, pp. 341-342 (2010).
Suzuki et al., "Stable Transgene Expression from HSV Amplicon Vectors in the Brain: Potential Involvement of Immunoregulatory Signals", Molecular Therapy (2008), 16(10):1727-1736.
Suzuki, et al.; "Two Routes for Remembering the Past"; Cell; vol. 147, pp. 493-495 (Oct. 28, 2011).
Swanson, "Lights, Opsins, Action! Optogenetics Brings Complex Neuronal Circuits into Sharper Focus", 2009, The Dana Foundation, [URL: http://www.dana.org/news/features/detail.aspx?id=24236], PDF File, pp. 1-3.
Swiss-Prot_Q2QCJ4, Opsin 1, Oct. 31, 2006, URL: http://www.ncbi.nlm.nig.gov/protein/Q2QCJ4.
Synapse, Chapter 13, http://michaeldmann.net/mann13.html, downloaded Apr. 2014.
Takahashi, et al., "Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined Factors", 2006, Cell, vol. 126, pp. 663-676.
Takahashi, et al."Diversion of the Sign of Phototaxis in a Chlamydomonas reinhardtii Mutant Incorporated with Retinal and Its Analogs," FEBS Letters, 1992, vol. 314, No. 3, pp. 275-279.
Tam, B. et al., "Identification of an Outer Segment Targeting Signal in the COOH Terminus of Rhodopsin Using Transgenic Xenopus laevis", The Journal of Cell Biology, 2000, vol. 151, No. 7, pp. 1369-1380.
Tamai, "Progress in Pathogenesis and Therapeutic Research in Retinitis Pigmentosa and Age Related Macular Degeneration", Nippon Ganka Gakkai Zasshi, vol. 108, No. 12, Dec. 2004 (Dec. 2004), pp. 750-769.
Tatarkiewicz, et al. "Reversal of Hyperglycemia in Mice After Subcutaneous Transplantation of Macroencapsulated Islets", Transplantation, 1999, vol. 67, No. 5: pp. 665-671.
Taurog et al., "HLA-B27 in inbred and non-inbred transgenic mice", J. Immunol., 1988, vol. 141, pp. 4020-4023.
Thomas et al., "Progress and Problems with the Use of Viral Vectors for Gene", Nat. Rev. Genet. (2003), 4(5):346-358.
Tomita, et al.; "Visual Properties of Transgenic Rats Harboring the Channelrhodopsin-2 Gene Regulated by the Thy-1.2 Promoter"; PLoS One; vol. 4, No. 11, 13 pages (Nov. 2009).
Tønnese, et al., "Optogenetic Control of Epileptiform Activity", PNAS, 2009, vol. 106, No. 29, pp. 12162-12167.
Tottene et al., "Familial Hemiplegic Migraine Mutations Increase Ca2+ Influx Through Single Human Cav2.1 Current Density in Neurons", PNAS USA, 2002, vol. 99, No. 20: pp. 13284-13289.
Towne et al., "Efficient transduction of non-human primate motor neurons after intramuscular delivery of recombinant AAV serotype 6", Gene Ther. (Jan. 2010), 17(1):141-6.
Towne et al., "Optogenetic control of targeted peripheral axons in freely moving animals", PLoS One (Aug. 2013), 8(8):e72691.
Towne et al., "Recombinant adeno-associated virus serotype 6 (rAAV2/6)-mediated gene transfer to nociceptive neurons through different routes of delivery", Mol Pain (Sep. 2009), 5:52.
Tsai, et al., "Phasic Firing in Dopaminergic Neurons in Sufficient for Behavioral Conditioning", Science, 2009, vol. 324, pp. 1080-1084.
Tsau et al. "Distributed Aspects of the Response to Siphon Touch in Aplysia: Spread of Stimulus Information and Cross-Correlation Analysis," The Journal of Neuroscience, 1994, vol. 14, No. 7, pp. 4167-4184.
Tsuchida; "Nervous Control of Micturition"; The Japanese Journal of Urology; vol. 80, No. 9, pp. 1257-1277 (1989).
Tye et. al., "Amygdala circuitry mediating reversible and bidirectional control of anxiety", Nature, 2011, vol. 471(7338): pp. 358-362.
Tye et. al., Supplementary Materials: "An optically-resolved microcircuit for bidirectional anxiety control", Nature, 2011, vol. 471(7338): pp. 358-362.
Tye, et al. "Optogenetic investigation of neural circuits underlying brain disease in animal models," Nature Reviews Neuroscience (Mar. 2012), 13(4):251-266.
U.S. Appl. No. 11/459,636, filed Jul. 24, 2006, published as US 2007-0261127.
U.S. Appl. No. 11/459,638, filed Jul. 24, 2006, published as US 2007-0054319.
U.S. Appl. No. 11/651,422, filed Jan. 9, 2007, published as US 2008-0085265.
U.S. Appl. No. 12/031,651, filed Feb. 14, 2008, issued as U.S. Pat. No. 8,401,609 on Mar. 19, 2013.
U.S. Appl. No. 12/185,624, filed Aug. 4, 2008, published as US 2009-0088680.
U.S. Appl. No. 12/187,927, filed Aug. 7, 2008, published as US 2009-0099038.
U.S. Appl. No. 12/263,026, filed Oct. 31, 2008, published as US 2009-0112133.
U.S. Appl. No. 12/263,044, filed Oct. 31, 2008, published as US 2009-0118800.
U.S. Appl. No. 12/522,520, filed Jan. 8, 2010, issued as U.S. Pat No. 8,398,692 on Mar. 19, 2013.
U.S. Appl. No. 12/522,528, filed Apr. 6, 2010, published as US 2010-0190229.
U.S. Appl. No. 12/715,259, filed Mar. 1, 2010, published as US 2010-0234273.
U.S. Appl. No. 12/988,567, filed Dec. 7, 2010, published as US 2011-0105998.
U.S. Appl. No. 12/993,605, filed Jan. 20, 2011, published as US 2011-0112179.
U.S. Appl. No. 12/996,753, filed Mar. 10, 2011, published as US 2011-0166632.
U.S. Appl. No. 12/997,140, filed Feb. 7, 2011, published as US 2011-0159562.
U.S. Appl. No. 12/997,158, filed Feb. 7, 2011, published as US 2011-0172653.
U.S. Appl. No. 13/128,979, filed Jul. 28, 2011, published as US 2011-0311489.
U.S. Appl. No. 13/208,419, filed Aug. 12, 2011, published as US 2011-0301529.
U.S. Appl. No. 13/299,727, filed Nov. 18, 2011, published as US 2012-0165904.
U.S. Appl. No. 13/555,981, filed Jul. 23, 2012, Deisseroth, et al.
U.S. Appl. No. 13/555,981, filed Jul. 23, 2013.
U.S. Appl. No. 13/577,565, filed Sep. 14, 2012, published as US 2013-0019325.
U.S. Appl. No. 13/622,809, filed Sep. 18, 2012.
U.S. Appl. No. 13/622,809, filed Sep. 19, 2012, Deisseroth, et al.
U.S. Appl. No. 13/623,612, filed Sep. 20, 2012, Deisseroth, et al.
U.S. Appl. No. 13/623,612, filed Sep. 20, 2013.
U.S. Appl. No. 13/718,243, filed Dec. 18, 2012, Deisseroth, et al.
U.S. Appl. No. 13/718,243, filed Dec. 18, 2012.
U.S. Appl. No. 13/763,119, filed Feb. 8, 2013, Deisseroth, et al.
U.S. Appl. No. 13/763,119, filed Feb. 8, 2013.
U.S. Appl. No. 13/763,132, filed Feb. 8, 2013, Deisseroth, et al.
U.S. Appl. No. 13/763,132, filed Feb. 8, 2013.
U.S. Appl. No. 13/772,732, filed Feb. 21, 2013, Deisseroth, et al.
U.S. Appl. No. 13/772,732, filed Feb. 21, 2013.
U.S. Appl. No. 13/822,703, filed Nov. 4, 2011.
U.S. Appl. No. 13/847,653, filed Mar. 20, 2013, Deisseroth, et al.
U.S. Appl. No. 13/847,653, filed Mar. 20, 2013.
U.S. Appl. No. 13/847,785, filed Mar. 20, 2013, Deisseroth, et al.
U.S. Appl. No. 13/847,785, filed Mar. 20, 2013.
U.S. Appl. No. 13/849,913, filed Mar. 25, 2013, Deisseroth, et al.
U.S. Appl. No. 13/849,913, filed Mar. 25, 2013.
U.S. Appl. No. 13/850,426, filed Mar. 26, 2013, Deisseroth, et al.
U.S. Appl. No. 13/850,426, filed Mar. 26, 2013.
U.S. Appl. No. 13/850,428, filed Mar. 26, 2013, Deisseroth, et al.
U.S. Appl. No. 13/850,428, filed Mar. 26, 2013.
U.S. Appl. No. 13/850,436, filed Mar. 26, 2013, Deisseroth, et al.
U.S. Appl. No. 13/850,436, filed Mar. 26, 2013.
U.S. Appl. No. 13/850,709, filed Mar. 26, 2013, Deisseroth, et al.
U.S. Appl. No. 13/850,709, filed Mar. 26, 2013.
U.S. Appl. No. 13/854,750, filed Apr. 1, 2013, Deisseroth, et al.
U.S. Appl. No. 13/854,750, filed Apr. 1, 2013.
U.S. Appl. No. 13/854,754, filed Apr. 1, 2013, Deisseroth, et al.
U.S. Appl. No. 13/854,754, filed Apr. 1, 2013.
U.S. Appl. No. 13/855,413, filed Apr. 2, 2013, Deisseroth, et al.
U.S. Appl. No. 13/855,413, filed Apr. 2, 2013.
U.S. Appl. No. 13/875,966, filed May 2, 2013, Deisseroth, et al.
U.S. Appl. No. 13/875,966, filed May 2, 2013.
U.S. Appl. No. 13/882,566, filed Nov. 4, 2011, Deisseroth, et al.
U.S. Appl. No. 13/882,566, filed Nov. 4, 2011.
U.S. Appl. No. 13/882,666, filed Nov. 4, 2011, Deisseroth, et al.
U.S. Appl. No. 13/882,666, filed Nov. 4, 2011.
U.S. Appl. No. 13/882,670, filed Nov. 4, 2011, Deisseroth, et al.
U.S. Appl. No. 13/882,670, filed Nov. 4, 2011.
U.S. Appl. No. 13/882,703, filed Nov. 4, 2011, Deisseroth, et al.
U.S. Appl. No. 13/882,719, filed Nov. 4, 2011, Deisseroth, et al.
U.S. Appl. No. 13/882,719, filed Nov. 4, 2011.
Ulmanen, et al. "Transcription and translation of foreign genes in Bacillus subtilis by the aid of a secretion vector," Journal of Bacteriology, 1985, vol. 162, No. 1: pp. 176-182.
Uniprot Accession No. P02945, integrated into the database on Jul. 21, 1986.
Van Der Linden, "Functional brain imaging and pharmacotherapy in social phobia: single photon emission computed tomography before and after Treatment with the selective serotonin reuptake inhibitor citalopram," Prog Neuro-psychopharmacol Biol Psychiatry, 2000, vol. 24, No. 3: pp. 419-438.
Vanin, et al. "Development of high-titer retroviral producer cell lines by using Cre-mediated recombination," Journal of Virology, 1997, vol. 71, No. 10: pp. 7820-7826.
Varo et al.,"Light-Driven Chloride Ion Transport by Halorhodopsin from Natronobacterium pharaonis. 2. Chloride Release and Uptake, Protein Conformation Change, and Thermodynamics", Biochemistry (1995), 34(44):14500-14507.
Verma, et al.; "Gene therapy—promises, problems and prospects"; Nature; vol. 389, pp. 239-242 (Sep. 1997).
Vetter, et al. "Development of a Microscale Implantable Neural Interface (MINI) Probe System," Proceedings of the 2005 IEEE, Engineering in Medicine and Biology 27th Annual Conference, Shanghai, China, Sep. 1-4, 2005.
Wagner, "Noninvasive Human Brain Stimulation", Annual Rev. Biomed. Eng. 2007. 9:I9.I-19.39.
Wall, "Transgenic livestock: Progress and prospects for the future", Theriogenology, 1996, vol. 45, pp. 57-68.
Wang et al. (2007) PNAS, vol. 104(19), 8143-8148. *
Wang et al. "Direct-current Nanogenerator Driven by Ultrasonic Waves," Science, 2007, vol. 316, pp. 102-105.
Wang et al., "Mrgprd-Expressing Polymodal Nociceptive Neurons Innervate Most Known Classes of Substantia Gelatinosa Neurons", J Neurosci (Oct. 2009), 29(42):13202-13209.
Wang et. al., "High-speed mapping of synaptic connectivity using photostimulation in Channelrhodopsin-2 transgenic mice", PNAS, 2007, vol. 104, No. 19, pp. 8143-8148.
Wang, et al., "High-speed mapping of synaptic connectivity using photostimulation in Channelrhodopsin-2 transgenic mice", Proceedings of the National Academy of Sciences, 2007, vol. 104, No. 19, pp. 8143-8148.
Wang, et al., "Molecular Determinants Differentiating Photocurrent Properties of Two Channelrhodopsins from Chlamydomonas", 2009, The Journal of Biological Chemistry, vol. 284, No. 9, pp. 5685-5696.
Wang, et al.; "Laser-evoked synaptic transmission in cultured hippocampal neurons expressing channelrhodopsin-2 delivered by adeno-associated virus"; Journal of Neuroscience Methods; vol. 183, pp. 165-175 (2009).
Wang, et al.; "Simultaneous phase and size control of upconversion nanocrystals through lanthanide doping"; Nature; vol. 463, No. 7284, pp. 1061-1065 (Feb. 25, 2010).
Ward, et al. "Construction and characterisation of a series of multi-copy promoter-probe plasmid vectors for Streptomyces using the aminoglycoside phosphotransferase gene from Tn5 as indicator", 1986, Mol. Gen. Genet., vol. 203: pp. 468-478.
Watson, et al. "Targeted transduction patterns in the mouse brain by lentivirus vectors pseudotyped with VSV, Ebola, Mokola, LCMV, or MuLV envelope proteins," Molecular Therapy, 2002, vol. 5, No. 5, pp. 528-537.
Weick et al. "Interactions with PDZ Proteins Are Required for L-Type Calcium Channels to Activate cAMP Response Element-Binding Protein-Dependent Gene Expression," The Journal of Neuroscience, 2003, vol. 23, No. 8, pp. 3446-3456.
Weiss, et al.; "Galanin: A Significant Role in Depression?"; Annals New York Academy of Sciences; vol. 863, No. 1, pp. 364-382 (1998).
Welberg; "CA1 triggers the trace"; Nature Reviews Neuroscience; vol. 12, 1 page (Nov. 9, 2011).
Wells et al. "Application of Infrared light for in vivo neural stimulation," Journal of Biomedical Optics, 2005, vol. 10(6), pp. 064003-1-064003-12.
Williams et al., "From optogenetic technologies to neuromodulation therapies", Sci Transl Med. (Mar. 2013), 5 (177):177ps6.
Winter, et al.; "Lesions of dopaminergic neurons in the substantia nigra pars compacta and in the ventral tegmental area enhance depressive-like behavior in rats"; Behavioural Brain Research; vol. 184, pp. 133-141 (2007).
Witten et. al., "Cholinergic Interneurons Control Local Circuit Activity and Cocaine Conditioning", Science, 2010, vol. 330, No. 6011: pp. 1677-1681.
Witten et. al., Supporting Online Material for: "Cholinergic Interneurons Control Local Circuit Activity and Cocaine Conditioning", Science, 2010, vol. 330: 17 pages.
Witten, et al.; "Cholinergic interneurons of the nucleus accumbens control local circuit activity and reward behavior"; Society for Neuroscience Abstract Viewer and Itinerary Planner & 40th Annual Meeting of the Society-for-Neuroscience; vol. 40, 2 pages (2010).
Written opinion of PCT Application No. PCT/US2011/059383 (dated May 9, 2012).
Xiong et al., "Interregional connectivity to primary motor cortex revealed using MRI resting state images", Hum Brain Mapp, 1999, 8(2-3):151-156.
Yamazoe, et al. "Efficient generation of dopaminergic neurons from mouse embryonic stem cells enclosed in hollow fibers", Biomaterials, 2006, vol. 27, pp. 4871-4880.
Yan et al., "Cloning and Characterization of a Human β, β-Carotene-15, 15′-Dioxygenase that is Highly Expressed in the Retinal Pigment Epithelium", Genomics, 2001, vol. 72: pp. 193-202.
Yizhar et al., "Optogenetics in neural systems", Neuron Primer, 2011, vol. 71, No. 1, pp. 9-34.
Yizhar et. al., "Neocortical excitation/inhibition balance in information processing and social dysfunction", Nature, 2011, vol. 477, pp. 171-178; and Supplemental Materials; 41 pages.
Yoon, et al., "A micromachined silicon depth probe for multichannel neural recording," IEEE Transactions Biomedical Engineering, 2000, vol. 47, No. 8, pp. 1082-1087.
Yoshimura, et al. "Excitatory cortical neurons form fine-scale functional networks", Nature, 2005, vol. 433: pp. 868-873.
Zacharias et al. "Recent advances in technology for measuring and manipulating cell signals," Current Opinion in Neurobiology, 2000, vol. 10: pp. 416-421.
Zemelman, et al. "Photochemical gating of heterologous ion channels: Remote control over genetically designated populations of neurons", PNAS, 2003, vol. 100, No. 3: pp. 1352-1357.
Zemelman, et al. "Selective Photostimulation of Genetically ChARGed Neurons", Neuron, 2002, vol. 33: pp. 15-22.
Zeng, et al.; "Activation of acid-sensing ion channels by localized proton transient reveals their role in proton signaling"; Scientific Reports; vol. 5, 14 pages (Sep. 15, 2015).
Zeng, et al.; "Proton production, regulation and pathophysiological roles in the mammalian brain"; Neuroscience Bulletin; vol. 28, No. 1, pp. 1-13 (Feb. 1, 2012).
Zhang "Multimodal fast optical interrogation of neural circuitry," Nature, 2007, vol. 446, pp. 633-641.
Zhang, et al. "Channelrhodopsin-2 and optical control of excitable cells," Nature Methods, 2006, vol. 3, No. 10, pp. 785-792.
Zhang, et al. "Red-Shifted Optogenetic Excitation: a Tool for Fast Neural Control Derived from Volvox carteri", Nature Neurosciences, 2008, vol. 11, No. 6, pp. 631-633.
Zhang, et al., "The Microbial Opsin Family of Optogenetic Tools", Cell, 2011, vol. 147, No. 7, pp. 1146-1457.
Zhang, et al.; "Optogenetic interrogation of neural circuits: Technology for probing mammalian brain structures"; Nature Protocols; vol. 5, No. 3, pp. 439-456 (Mar. 1, 2010).
Zhao, et al., "Improved Expression of Halorhodopsin for Light-Induced Silencing of Neuronal Activity", Brain Cell Biology, 2008, vol. 36 (1-4), pp. 141-154.
Zrenner, E., "Will Retinal Implants Restore Vision?" Science, 2002, vol. 295, No. 5557, pp. 1022-1025.
Zufferey, et al. "Self-Inactivating Lentivirus Vector for Safe and Efficient In Vivo Gene Delivery", Journal of Virology, 1998, vol. 72, No. 12, pp. 9873-9880.

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11294165B2 (en) 2017-03-30 2022-04-05 The Board Of Trustees Of The Leland Stanford Junior University Modular, electro-optical device for increasing the imaging field of view using time-sequential capture

Also Published As

Publication number Publication date
US20190046554A1 (en) 2019-02-14
EP2635295B1 (en) 2017-12-20
AU2011323228B2 (en) 2016-11-10
AU2011323228A1 (en) 2013-05-09
CA2816972A1 (en) 2012-05-10
JP6328424B2 (ja) 2018-05-23
CN103298480A (zh) 2013-09-11
ES2661093T3 (es) 2018-03-27
AU2017200881B2 (en) 2019-03-07
EP2635295A4 (en) 2014-04-30
CN106376525A (zh) 2017-02-08
EP2635295A1 (en) 2013-09-11
JP6328424B6 (ja) 2018-07-11
WO2012061681A1 (en) 2012-05-10
US20130343998A1 (en) 2013-12-26
CA2816972C (en) 2019-12-03
JP2014500717A (ja) 2014-01-16
AU2017200881A1 (en) 2017-03-02
CN103298480B (zh) 2016-10-12

Similar Documents

Publication Publication Date Title
AU2017200881B2 (en) Control and characterization of memory function
AU2017279749B2 (en) Optogenetic control of reward-related behaviors
US20180333456A1 (en) Optically-controlled cns dysfunction
AU2011323199B2 (en) Stabilized step function opsin proteins and methods of using the same
US10974064B2 (en) Optogenetic control of behavioral state
Lopes Regulation of dopamine release by striatal GABA and acetylcholine in health and disease

Legal Events

Date Code Title Description
AS Assignment

Owner name: THE BOARD OF TRUSTEES OF THE LELAND STANFORD JUNIO

Free format text: ASSIGNMENT OF ASSIGNORS INTEREST;ASSIGNORS:DEISSEROTH, KARL;GOSHEN, INBAL;SIGNING DATES FROM 20130519 TO 20130705;REEL/FRAME:030972/0623

STCF Information on status: patent grant

Free format text: PATENTED CASE

CC Certificate of correction
FEPP Fee payment procedure

Free format text: ENTITY STATUS SET TO SMALL (ORIGINAL EVENT CODE: SMAL); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

MAFP Maintenance fee payment

Free format text: PAYMENT OF MAINTENANCE FEE, 4TH YR, SMALL ENTITY (ORIGINAL EVENT CODE: M2551); ENTITY STATUS OF PATENT OWNER: SMALL ENTITY

Year of fee payment: 4